Benzoheterocyclic compounds and use thereof

ABSTRACT

Disclosed are compound of formula (I) and pharmaceutically accepted salts and prodrugs thereof, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1  and X 2  is as defined in the description. These compounds are protein kinases inhibitors, especially the inhibitors of Mek, which are useful in the treatment of cancers and inflammation of mammals. Disclosed are the treatment methods of cancers and inflammation of mammals as well as pharmaceutical compositions comprising the compounds described herein. The preparation of benzoheterocyclic compounds are disclosed. Disclosed are the preparation of potential drug candidates, such as benzooxazol, benzothiazol, benzothiadiazol and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase application under 35 U.S.C. §371 of International Application No. PCT/CN2013/000037, filed Jan. 16, 2013, and claims the benefit of priority to People's Republic of China Patent Application No. 201210014021.X filed Jan. 17, 2012, People's Republic of China Patent Application No. 201210189086.8 filed Jun. 8, 2012, People's Republic of China Patent Application No. 201210190520.4 filed Jun. 8, 2012, and People's Republic of China Patent Application No. 201210189087.2 filed Jun. 8, 2012, the disclosures of each of which are hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to benzoheterocyclic compounds such as benzothiadiazole, benzoxazole and benzothiazole derivatives, which are inhibitors of protein kinases such as MEK. The compounds may be useful in the treatment of conditions or disorders where the MEK cascade is implicated such as cancer and inflammatory diseases.

BACKGROUND OF THE INVENTION

Cell signaling through growth factor receptors and protein kinases is an important regulator of cell growth, proliferation and differentiation. In normal cell growth, factors (i.e. PDGF or EGF and others), through receptor activation (i.e. ErbB2, EGFR, PDGFR), activate MAP (Mitogen-activating protein) kinase pathways. One of the most important and most well understood MAP kinase pathways involved in normal and uncontrolled cell growth is the Ras/Raf/Mek/Erk kinase pathway. In proliferative diseases, genetic mutations and/or overexpression of the growth factor receptors, downstream signaling proteins, or protein kinases involved in the kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation. For example, some cancers contain mutations which results in the activation of this pathway due to continuous production of growth factors. The statistics show that mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers. Recently, bRaf mutations have been identified in more than 60% of malignant melanoma. Studies of primary tumor samples and cell lines have also shown constitutive or overactivation of the Ras/Raf/Mek/Erk pathway in cancers of pancreas, colon, lung, ovary and kidney.

As constitutive or overactivation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed to be beneficial in hyperproliferative diseases. Mek is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates for Mek phosphorylation are the MAP kinases, Erk 1 and 2. Hence, inhibition of MEK would block Ras/Raf/Mek/Erk pathway and result in cell growth inhibition, especially the cell growth due to the overactivation of Ras or Raf. Meanwhile Mek is also related to inflammatory disease and symptoms, including acute and chronic inflammation.

Inhibitors of Mek have shown some effects in clinical experiments of nude mice. Recently, some Mek inhibitors have been applied at clinical experiments of people. Therefore, Mek is a potential new target and more and more Mek inhibitors are developed and reported, for example, WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/41003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; WO 03/077855; WO 03/077914; WO 05/023251; WO 05/023759; WO 05/051300; WO 05/051301; WO 05/051302; WO 05/051906; WO 05/000818; WO 05/007616; WO 05/009975; WO 05/046665; WO 06/134469; WO 07/044,084; WO 07/014,011; WO 07/121,269; WO 07/121,481; WO 07/071,951; WO 07/044,515; WO 08/021,389; WO 08/076,415; WO 08/089,459; WO 08/078,086; WO 08/120,004; WO 08/124,085; WO 08/125,820; WO 09/018,238; WO 09/074,827; WO 09/013,426; WO 09/093,008; WO 09/093,009; WO 09/093,013; WO 09/153,554 and so on.

However, many known MEK inhibitors suffer from weak inhibitory activity, intolerable toxicity or lack of desirable pharmaceutical properties. Thus, there remains a need for potent inhibitors of MEK with appropriate pharmaceutical properties for clinical applications.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided is a compound of the formula (I):

or a salt, solvate or prodrug thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto;

provided that if X¹ is CH, X² is O or S, R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, provided is a compound of the formula (J):

or a salt, solvate or prodrug thereof, wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (I).

In another aspect, provided is any one of the MEK inhibitor compounds described herein present in a substantially pure form.

Also provided are pharmaceutical compositions and/or formulations comprising any one of the compounds described herein and a carrier (e.g., a pharmaceutically acceptable carrier). In some embodiments, the formulation is suitable for administration to an individual. In some embodiments, the formulation comprises an effective amount of any one of the compounds described herein and a carrier (e.g., a pharmaceutically acceptable carrier). In another aspect, provided are pharmaceutical formulations comprising a MEK inhibitor compound described herein or a MEK inhibitor compound described herein in combination with a pharmaceutically acceptable carrier.

In another aspect, provided are methods for the treatment and/or prevention of a disease, condition, or disorder where the MEK pathway cascade is implicated, such as a disease, condition, or disorder mediated by MEK, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. In some embodiments, the disease or condition is cancer, chronic inflammatory disease, a skin disease, diabetes, an eye disease, vasculogenesis, angiogenesis or chronic pain. In some embodiments, the disease or condition is rheumatoid arthritis or inflammatory bowel disease. In some embodiments, the disease or condition is a cancer such as colon cancer, colorectal cancer, lung cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer or skin cancer.

Also provided is use of compounds detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition which can be ameliorated by inhibition of MEK in an individual, such as a mammal (e.g., human), in need thereof.

Kits comprising a compound as described herein and instructions for use are also provided. In one aspect, provided are kits for the treatment or prevention in an individual of a disease or condition mediated by MEK, comprising any one of the compounds detailed herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and packaging. In some embodiments, the kit comprises a formulation of any one of the compounds described herein and packaging.

Further provided are methods and processes of making compounds described herein, or a salt (including a pharmaceutically acceptable salt), solvate or prodrug thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the anti-tumor effect of Compounds 1, 3, 9, 11, 17 and 19 in a mouse xenograft model of human colon HT-29 cells.

FIG. 2 shows the anti-tumor effect of Compounds 1, 3, 9, 11, 17 and 19 in a COLO-205 xenograft model.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

The term “halo” or “halogen”, by itself or as part of another substituent, refers to and includes fluoro, chloro, bromo and iodo.

The term “alkyl”, by itself or as part of another substituent, refers to and includes saturated linear (i.e. unbranched) or branched hydrocarbon radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Particular alkyl groups are those having 1 to 10 carbon atoms (a “C₁-C₁₀ alkyl”). More particular alkyl groups are those having 1 to 6 carbon atoms (a “C₁-C₆ alkyl”), 1 to 4 carbon atoms (a “C₁-C₄ alkyl”), 1 to 3 carbon atoms (a “C₁-C₃ alkyl”) or 1 to 2 carbon atoms (a “C₁-C₂ alkyl”). Examples of “C₁-C₁₀ alkyl” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “alkenyl”, by itself or as part of another substituent, refers to and includes unsaturated linear (i.e. unbranched) or branched hydrocarbon radicals containing at least one carbon-carbon double bond, having the number of carbon atoms designated (i.e., C₂-C₁₀ means two to ten carbons). Particular alkenyl groups are those having 2 to 10 carbon atoms (a “C₂-C₁₀ alkenyl”). More particular alkenyl groups are those having 2 to 8 carbon atoms (a “C₂-C₈ alkenyl”) or 2 to 6 carbon atoms (a “C₂-C₆ alkenyl”). Examples of “C₂-C₁₀ alkenyl” include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, and the like.

The term “alkynyl”, by itself or as part of another substituent, refers to and includes unsaturated linear (i.e. unbranched) or branched hydrocarbon radicals containing at least one carbon-carbon triple bond, having the number of carbon atoms designated (i.e., C₂-C₁₀ means two to ten carbons). Particular alkynyl groups are those having 2 to 10 carbon atoms (a “C₂-C₁₀ alkynyl”). More particular alkenyl groups are those having 2 to 8 carbon atoms (a “C₂-C₈ alkynyl”) or 2 to 6 carbon atoms (a “C₂-C₆ alkynyl”). Examples of “C₂-C₁₀ alkynyl” include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, but-1-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, 1-methyl-2-propynyl, pent-1-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, hex-1-yn-1-yl, hex-2-yn-1-yl, hex-3-yn-1-yl, hex-4-yn-1-yl, hex-5-yn-1-yl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, and the like.

The term “cycloalkyl”, by itself or as part of another substituent, refers to and includes saturated monocyclic hydrocarbon radicals, having the number of carbon atoms designated (i.e., C₃-C₁₀ means three to ten carbons). Particular cycloalkyl groups are those having 3 to 10 carbon atoms (a “C₃-C₁₀ cycloalkyl”). More particular cycloalkyl groups are those having 3 to 8 carbon atoms (a “C₃-C₈ cycloalkyl”), 3 to 6 carbon atoms (a “C₃-C₆ cycloalkyl”) or 3 to 4 carbon atoms (a “C₃-C₄ cycloalkyl”). Examples of “C₃-C₁₀ cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term “aryl”, by itself or as part of another substituent, refers to and includes monocyclic or polycyclic aromatic hydrocarbon radicals, having the number of annular carbon atoms designated (i.e., C₆-C₁₄ means six to fourteen carbons). Particular aryl groups are those having 6 to 14 annular carbon atoms (a “C₆-C₁₄ aryl”). Examples of “C₆-C₁₄ aryl” include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. In some embodiments, an aryl may contain a single ring (e.g., phenyl). In some embodiments, an aryl may contain multiple rings (e.g., biphenyl). In some embodiments, an aryl may contain multiple condensed rings where at least one of the condensed rings is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl and naphthyl).

The term “C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀ alkyl moiety which is substituted with a C₃-C₁₀ cycloalkyl moiety. Examples of “C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl” include, but are not limited to, cyclopropylmethyl and the like.

The term “C₆-C₁₄ aryl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀ alkyl moiety which is substituted with a C₆-C₁₄ aryl moiety. Examples of “C₆-C₁₄ aryl C₁-C₁₀ alkyl” include, but are not limited to, benzyl, phenylethyl, and the like.

The term “heterocyclyl” or “heterocycle” as used herein refers to monocyclic or bicyclic radicals which may be fully saturated, partially saturated, or fully unsaturated or aromatic, having the number of annular carbon atoms designated (i.e., C₃-C₁₀ means three to ten annular carbon atoms) and containing at least one or more of the same or different heteroatoms selected from N, S or O, provided that at least one annular carbon atom is present and two annular oxygen atoms, if present, do not occupy directly neighboring positions. A “heterocyclyl” or “heterocycle” may be a 3 to 15-membered saturated or partially unsaturated ring containing 1 to 4 heteroatoms selected from O, S and N, where the ring may be monocyclic, bicyclic or tricyclic, contain at least one annular carbon atom and 1 to 3 nitrogen atoms, and/or 1 oxygen or sulfur atom or 1 or 2 oxygen and/or sulfur atoms; provided that when more than one annular oxygen atoms are present, they do not occupy directly neighboring positions. Examples of “heterocyclyl” or “heterocycle” include, but are not limited to, 2-oxiranyl, 2-aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolinyl, 4-isoxazolinyl, 5-isoxazolinyl, 3-isothiazolinyl, 4-isothiazolinyl, 5-isothiazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 2-oxazolinyl, 4-oxazolinyl, 5-oxazolinyl, 2-thiazolinyl, 4-thiazolinyl, 5-thiazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-triazol-2-yl, 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,4-dihydrothiophen-2-yl, 2,4-dihydrothiophen-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazolin-1-yl, 2,3-dihydropyrazolin-2-yl, 2,3-dihydropyrazolin-3-yl, 2,3-dihydropyrazolin-4-yl, 2,3-dihydropyrazolin-5-yl, 3,4-dihydropyrazoline-1-yl, 3,4-dihydropyrazolin-3-yl, 3,4-dihydropyrazolin-4-yl, 3,4-dihydropyrazolin-5-yl, 4,5-dihydropyrazolin-1-yl, 4,5-dihydropyrazolin-3-yl, 4,5-dihydropyrazolin-4-yl, 4,5-dihydropyrazolin-5-yl, 2,3-dihydrooxazolin-2-yl, 2,3-dihydrooxazolin-3-yl, 2,3-dihydrooxazolin-4-yl, 2,3-dihydrooxazolin-5-yl, 3,4-dihydrooxazolin-2-yl, 3,4-dihydrooxazolin-3-yl, 3,4-dihydrooxazolin-4-yl, 3,4-dihydrooxazolin-5-yl, 4,5-dihydrooxazolin-2-yl, 4,5-dihydrooxazolin-3-yl, 4,5-dihydrooxazolin-4-yl, piperidin-2-yl, piperidine-3-yl, piperidine-4-yl, 1,3-dioxane-5-yl, tetrahydropyran-2-yl, tetrahydropyran-4-yl, tetrahydrothiophen-2-yl, hexahydrodiazin-3-yl, hexahydrodiazin-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-2-yl, 1,3,5-triazinan-2-yl, 1,2,4-triazinan-3-yl, and the like.

The term “heteroaryl” as used herein refers to aromatic heterocyclyl or heterocycle as defined herein. Examples of “heteroaryl” include, but are not limited to, 2-furanyl, 3-furanyl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-triazol-2-yl, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 1,2,4-triazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, diazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4,5-tetrazin-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzo[d]imidazol-1-yl, benzo[d]imidazol-2-yl, benzo[d]imidazol-4-yl, benzo[d]imidazol-5-yl, indazol-1-yl, indazol-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzo[d]oxazol-2-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, benzo[d]oxazol-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, and the like.

The term “heterocyclyl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀ alkyl moiety which is substituted with a heterocyclyl moiety. Examples of “heterocyclyl C₁-C₁₀ alkyl” include, but are not limited to, tetrahydrofuranylmethyl and the like.

The term “heteroaryl C₁-C₁₀ alkyl” as used herein refers to a C₁-C₁₀ alkyl moiety which is substituted with a heteroaryl moiety. Examples of “heteroaryl C₁-C₁₀ alkyl” include, but are not limited to, oxazolylmethyl, pyridylethyl, and the like.

The term “solvate” refers to an aggregate formed by a solute molecule (such a compound of the invention) or ion with one or more solvent molecules via intermolecular forces such as Coulomb force, Van der Waals force, charge-dipole interactions and hydrogen bonding. When the solvent is water, the solvate is referred to as “hydrate.”

Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a human. The invention may find use in both human medicine and in the veterinary context.

The term “administration” and variants thereof (e.g., “administering”) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.

The term “therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term “treatment” refers to the treatment of a mammal afflicted with a pathological condition and refers to an effect that alleviates the condition, e.g., by killing the cancerous cells, but also to an effect that results in the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.

The term “prevention” includes providing prophylaxis with respect to occurrence or recurrence of a disease in an individual. An individual may be predisposed to, susceptible to the disease, or at risk of developing the disease, but has not yet been diagnosed with the disease.

The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Unless indicated otherwise, the term “pharmaceutically acceptable salt” as used herein, refers to salts which are suitable for use in contact with the tissues of a subject (e.g., human) without excessive adverse effect. In some embodiments, pharmaceutically acceptable salts include salts of a compound of the invention having an acidic group (for example, but not limited to, potassium salts, sodium salts, magnesium salts, calcium salt, and the like) or a basic group (for example, but not limited to, sulfate, hydrochloride, phosphate, nitrate, carbonate, and the like).

Compounds

Compounds according to the invention are detailed herein, including in the Brief Summary of the Invention and the appended claims. The invention embraces all compounds detailed herein, including any synthetic intermediates and uses thereof. The invention includes the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans), salts and solvates of the compounds described herein, as well as methods of making such compounds.

In one aspect, provided is a compound of the formula (I):

or a salt, prodrug or solvate thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, alkylthio, halo-substituted C₁-C₁₀)alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, provided that if X¹ is CH, X² is O or S, R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In another aspect, provided is a compound is of the formula (I):

or a salt, prodrug or solvate thereof, wherein:

X¹ is CR¹¹ or N;

X² is O, S or carbonyl;

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl;

each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R⁹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₆-C₁₄ aryl;

R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl, halo, C₁-C₁₀ alkoxy or C₁-C₁₀ alkylthio;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto;

provided that if X¹ is CH, X² is O or S, R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R¹⁰ or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein X¹ is N or CR¹¹. In some embodiments, X¹ is N. In some embodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In some of these embodiments, R¹¹ is hydrogen. In some of these embodiments, R¹¹ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In some other embodiments, R¹¹ is halo, C₁-C₁₀ alkoxy or C₁-C₁₀ alkylthio.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein X² is O, S or carbonyl. In some embodiments, X² is S. In some embodiments, X² is O. In some embodiments, X² is carbonyl.

It is intended and understood that each and every variations of X² described for the formula (I) may be combined with each and every variations of X¹ described for the formula (I) as if each and every combinations are individually described. For example, in some embodiments, X¹ is N and X² is S. In some embodiments, X¹ is N and X² is O or carbonyl. In some embodiments, X¹ is CR¹¹ and X² is O or S. In one variation, X¹ is CR¹¹ and X² is O. In another variation, X¹ is CR¹¹ and X² is S. In some embodiments, X¹ is CH and X² is O or S. In one variation, X¹ is CH and X² is O. In another variation, X¹ is CH and X² is S.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R¹ is hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R¹ is halo (e.g., fluoro or chloro). In some embodiments, R¹ is nitro, azido, hydroxy, amino or carboxy. In some embodiments, R¹ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy C₁-C₁₀ alkylthio or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R¹ is unsubstituted or substituted C₁-C₁₀ alkyl, unsubstituted or substituted C₂-C₁₀ alkenyl, unsubstituted or substituted C₂-C₁₀ alkynyl or unsubstituted or substituted C₃-C₁₀ cycloalkyl. In some embodiments, R¹ is unsubstituted C₁-C₁₀ alkyl (e.g., methyl).

In some embodiments, R¹ is hydrogen, halo or C₁-C₆ alkyl. In some embodiments, R¹ is hydrogen, halo or C₁-C₄ alkyl. In some embodiments, R¹ is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In some embodiments, R¹ is hydrogen, fluoro, chloro or methyl.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R² is hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, alkylthio, halo-substituted alkylthio, amino, carboxy, alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R² is hydrogen. In some embodiments, R² is halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted alkoxy, acyloxy, alkylthio, halo-substituted alkylthio, amino or carboxy. In some embodiments, R² is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl.

In some embodiments, R² is hydrogen, halo or C₁-C₆ alkyl. In some embodiments, R² is hydrogen, halo or C₁-C₄ alkyl. In some embodiments, R² is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In some embodiments, R² is hydrogen, fluoro, chloro or methyl.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted alkoxy, acyloxy, mercapto, alkylthio, halo-substituted alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R³ is halo or cyano. In some embodiments, R³ is halo (e.g., iodo or bromo). In some embodiments, R³ is nitro, azido, hydroxy or mercapto, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b). In some of these embodiments, R³ is —SO₂R^(a) where R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl. In one variation, R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R³ is —SO₂N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl. In one variation, R³ is —SO₂N(R^(c))R^(d) where each R^(c) and R^(d) is independently unsubstituted or substituted C₁-C₁₀ alkyl. In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl. In one variation, R³ is —N(R^(c))R^(d) where each R^(c) and R^(d) is independently hydrogen or methyl. In one particular variation, R³ is NMe₂. In some of these embodiments, R³ is —C(O)OR^(b) where R^(b) is hydrogen or C₁-C₁₀ alkyl. In one variation, R³ is —C(O)OR^(b) where R^(b) is hydrogen (i.e., R³ is carboxy). In another variation, R³ is —C(O)OR^(b) where R^(b) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., methyl or ethyl). In some embodiments, R³ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy (e.g., trifluoromethoxy), acyloxy, C₁-C₁₀ alkylthio (e.g., methylthio), or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R³ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R³ is unsubstituted or substituted C₁-C₁₀ alkyl, such as halo-substituted C₁-C₁₀ alkyl (e.g., trifluoromethyl).

In some embodiments, R³ is hydrogen, halo, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo-substituted C₁-C₆ alkyl, C₁-C₆ alkylthio, halo-substituted C₁-C₆ alkoxy or halo-substituted C₁-C₆ alkylthio. In some embodiments, R³ is fluoro, chloro, bromo, iodo, C₁-C₄ alkyl, halo-substituted C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, halo-substituted C₁-C₄ alkoxy or halo-substituted C₁-C₄ alkylthio. In some embodiments, R³ is bromo, iodo, C₁-C₂ alkylthio, halo-substituted C₁-C₂ alkylthio, C₁-C₂ alkoxy, halo-substituted C₁-C₂ alkoxy, C₁-C₂ alkyl or halo-substituted C₁-C₂ alkyl. In some embodiments, R³ is bromo, iodo, methyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy or trifluoromethylthio.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R⁴ is hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is halo, nitro, azido, hydroxy, amino or carboxy. In some embodiments, R⁴ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R⁴ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl.

In some embodiments, R⁴ is hydrogen, halo or C₁-C₆ alkyl. In some embodiments, R⁴ is hydrogen or C₁-C₄ alkyl. In some embodiments, R⁴ is hydrogen or C₁-C₂ alkyl. In some embodiments, R⁴ is hydrogen.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R⁵ is hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl. In some embodiments, R⁵ is hydrogen or halo or unsubstituted or substituted C₁-C₁₀ alkyl. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is fluoro. In some embodiments, R⁵ is C₁-C₁₀ alkyl (e.g., methyl). In some embodiments, R⁵ is halo, nitro, azido, hydroxy, amino or carboxy. In some embodiments, R⁵ is C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio or halo-substituted C₁-C₁₀ alkylthio. In some embodiments, R⁵ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl.

In some embodiments, R⁵ is hydrogen, halo or C₁-C₆ alkyl. In some embodiments, R⁵ is hydrogen, halo or C₁-C₄ alkyl. In some embodiments, R⁵ is hydrogen, fluoro, chloro, bromo or C₁-C₂ alkyl. In some embodiments, R⁵ is hydrogen, fluoro, chloro or methyl.

It is intended and understood that each and every variations of R¹, R², R³, R⁴ or R⁵ described for the formula (I) may be combined with each and every variations of another one or more of R¹, R², R³, R⁴ and R⁵ and/or each and every variations of X¹ and X² described for the formula (I) as if each and every combinations are individually described. For example, in some embodiments, provided is a compound of the formula (I), or a salt, prodrug or solvate thereof, where X¹ is N, X² is S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is N, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is N, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen and R⁵ is fluoro. In some embodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, X² is S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen and R⁵ is fluoro. In some embodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, X² is O, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is O, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is O, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen and R⁵ is fluoro.

In some embodiments, the compound is of the formula (I), or a salt, prodrug or solvate thereof, wherein R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)R⁹ or —NHSO₂R¹⁰. In some embodiments, R⁶ is —C(O)OR⁷. In some embodiments, R⁶ is —C(O)NR⁷R⁸. In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷ where each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some of these embodiments, R⁷ is hydrogen, unsubstituted or substituted C₁-C₁₀ alkyl or unsubstituted or substituted C₃-C₁₀ cycloalkyl. In some embodiments, R⁷ is C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl (e.g., cyclopropylmethyl). In some of these embodiments, R⁷ is substituted C₁-C₁₀ alkyl, such as C₁-C₁₀ alkyl substituted with at least one hydroxy group. In some of these embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₆ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of these embodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl, (R)-3-hydroxy-2-methylpropyl, (S)-3-hydroxy-2-methylpropyl, (R)-2,3-dihydroxypropyl, (S)-2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is unsubstituted or substituted C₂-C₁₀ alkenyl or unsubstituted or substituted C₂-C₁₀ alkynyl. In some of these embodiments, R⁷ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some of these embodiments, R⁸ is hydrogen or unsubstituted or substituted C₁-C₁₀ alkyl. In some of these embodiments, R⁸ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some embodiments, R⁶ is —C(O)R⁹ where R⁹ is unsubstituted or substituted C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some embodiments, R⁶ is —NHSO₂R¹⁰ where R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In some of these embodiments, R¹⁰ is unsubstituted or substituted C₁-C₁₀ alkyl or optionally substituted C₃-C₁₀ cycloalkyl. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl or C₃-C₁₀ cycloalkyl (e.g., cyclopropyl). In some of these embodiments, R¹⁰ is unsubstituted or substituted C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl, such as C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with at least one hydroxy group. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with 1 or 2 hydroxy groups (e.g., 1-(2,3-dihydroxypropyl)cyclopropyl). In some of these embodiments, R¹⁰ is (R)-1-(2,3-dihydroxypropyl)cyclopropyl) or (S)-1-(2,3-dihydroxypropyl)cyclopropyl). In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl.

In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷, —C(O)NR⁷R⁸ or —NHSO₂R¹⁶; each R⁷ and R⁸ is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl or C₁-C₆ alkyl C₃-C₆ cycloalkyl; and R¹⁶ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl or C₁-C₆ alkyl C₃-C₆ cycloalkyl; where each of the C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl C₁-C₆ alkyl and C₁-C₆ alkyl C₃-C₆ cycloalkyl groups may be unsubstituted or substituted with one or more groups selected from the group consisting of hydroxy and mercapto. In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷, —C(O)NR⁷R⁸ or —NHSO₂R¹⁶; each R⁷ and R¹⁶ is independently C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl C₁-C₄ alkyl or C₁-C₄ alkyl C₃-C₄ cycloalkyl, where each of the C₁-C₄ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl C₁-C₄ alkyl or C₁-C₄ alkyl C₃-C₄ cycloalkyl groups may be unsubstituted or substituted with 1 to 6 hydroxy groups; and R⁸ is hydrogen or C₁-C₄ alkyl. In some embodiments, R⁶ is —C(O)N(R⁸)OR⁷ or —NHSO₂R¹⁶; each R⁷ and R¹⁰ is independently C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl C₁-C₃ alkyl or C₁-C₃ alkyl C₃-C₄ cycloalkyl, where each of the C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkyl C₁-C₃ alkyl or C₁-C₃ alkyl C₃-C₄ cycloalkyl groups may be unsubstituted or substituted with 1 to 3 hydroxy groups; and R⁸ is hydrogen. In some embodiments, R⁶ is —C(O)NHOR⁷ or —NHSO₂R¹⁶ where each R⁷ and R¹⁰ is independently selected from the group consisting of 2-hydroxyethyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 3-hydroxy-2-methylpropyl, cyclopropyl and 1-(2,3-dihydroxypropyl)cyclopropyl.

It is intended and understood that each and every variations of R⁶ described for the formula (I) may be combined with each and every variations of X¹, X², R¹, R², R³, R⁴ and/or R⁵ described for the formula (I) as if each and every combinations are individually described. For example, in some embodiments, provided is a compound of the formula (I), or a salt, prodrug or solvate thereof, where X¹ is N or CR¹¹ where R¹¹ is H, X² is O or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxy groups and R⁸ is hydrogen. In some of these embodiments, X¹ is N, X² is S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOR⁷ where R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of these embodiments, X¹ is N, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOCH₂CH₂OH. In some of these embodiments, X¹ is N, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOCH₂CH₂OH. In some embodiments, X¹ is CR¹¹ where R¹¹ is hydrogen, X² is O or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro and R⁶ is —C(O)NHOR⁷ where R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of these embodiments, X¹ is CH, X² is S, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen, R⁵ is fluoro, and R⁶ is —C(O)NHOCH₂CH₂OH. In some of these embodiments, X¹ is CH, X² is S, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen and R⁵ is fluoro. In some of these embodiments, X¹ is CH, X² is O, R¹ is fluoro, R² is hydrogen, R³ is iodo, R⁴ is hydrogen, R⁵ is fluoro, and R⁶ is —C(O)NHOCH₂CH₂OH. In some of these embodiments, X¹ is CH, X² is O, R¹ is chloro, R² is hydrogen, R³ is bromo, R⁴ is hydrogen, R⁵ is fluoro, and R⁶ is —C(O)NHOCH₂CH₂OH.

Also provided is a compound of the formula (I-1):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound of the formula (I-1) is a compound of the formula (I-1-a), (I-1-b), (I-1-c) or (I-1-d):

or a salt, prodrug or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined for the formula (I-1).

In some embodiments, the compound is of the formula (I-1), (I-1-a), (I-1-b), (I-1-c) or (I-1-d), or a salt, prodrug or solvate thereof, wherein R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸, where applicable, are as defined for the formula (I) or any applicable variations thereof.

In some embodiments, the compound of the formula (I-1) is a compound of the formula (I-1-e):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁶ are as defined for the formula (I), (I-1), or any applicable variations thereof. In some particular embodiments of the compound of the formula (I-1-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selected from the group consisting of:

and R¹, R³ and R⁵ are as described in Table 1.

TABLE 1 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me F I H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H F CF₃ F F CF₃ Me F CF₃ H Cl Br F Cl Br Me Cl Br H Cl I F Cl I Me Cl I H Cl SMe F Cl SMe Me Cl SMe H Cl OCF₃ F Cl OCF₃ Me Cl OCF₃ H Cl CF₃ F Cl CF₃ Me Cl CF₃ H Me Br F Me Br Me Me Br H Me I F Me I Me Me I H Me SMe F Me SMe Me Me SMe H Me OCF₃ F Me OCF₃ Me Me OCF₃ H Me CF₃ F Me CF₃ Me Me CF₃ H

Also provided is a compound of the formula (I-2):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I-2) wherein R¹, R², R³, R⁴, R⁵, R⁶ and R¹¹ are as defined for the formula (I-2) provided that if R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R⁷ where R⁷ is as defined for the formula (I-2), or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, the compound of the formula (I-2) is a compound of the formula (I-2-a), (I-2-b), (I-2-c) or (I-2-d):

or a salt, prodrug or solvate thereof, wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹¹ are as defined for the formula (I-2).

In some embodiments, the compound is of the formula (I-2), (I-2-a), (I-2-b), (I-2-c) or

(I-2-d), or a salt, prodrug or solvate thereof, wherein R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹¹, where applicable, are as defined for the formula (I) or any applicable variations thereof.

In some embodiments, the compound of the formula (I-2) is a compound of the formula (I-2-e):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁶ are as defined for the formula (I), (I-2), or any applicable variations thereof. In some particular embodiments of the compound of the formula (I-2-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selected from the group consisting of:

and R¹, R³ and R⁵ are as specified in Table 2.

TABLE 2 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me F I H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H F CF₃ F F CF₃ Me F CF₃ H Cl Br F Cl Br Me Cl Br H Cl SMe F Cl I Me Cl I H Cl OCF₃ F Cl SMe Me Cl SMe H Cl CF₃ F Cl OCF₃ Me Cl OCF₃ H Me Br F Cl CF₃ Me Cl CF₃ H Me SMe F Me Br Me Me Br H Me OCF₃ F Me I Me Me I H Me CF₃ F Me SMe Me Me SMe H Me OCF₃ H Me OCF₃ Me Me CF₃ H Me CF₃ Me

Also provided is a compound of the formula (I-3):

or a salt, prodrug or solvate thereof, wherein:

R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, carboxy, —OC(O)H, amino, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl;

R⁶ is —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)N(R⁸)OR⁷, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), or —NHSO₂R⁷;

each R⁷ and R⁸ is independently hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl;

R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl;

wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.

In some embodiments, the compound is of the formula (I-3) wherein R¹, R², R³, R⁴, R⁵, R⁶ and R¹¹ are as defined for the formula (I-3) provided that if R¹ is methyl or chloro, R² is hydrogen and R³ is iodo, then R⁶ is —NHSO₂R⁷ where R⁷ is as defined for the formula (I-3), or —C(O)N(R⁸)OR⁷ where R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group.

In some embodiments, the compound of the formula (I-3) is a compound of the formula (I-3-a), (I-3-b), (I-3-c) or (I-3-d):

or a salt, prodrug or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹¹ are as defined for the formula (I-3).

In some embodiments, the compound is of the formula (I-3), (I-3-a), (I-3-b), (I-3-c) or (I-3-d), or a salt, prodrug or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹¹, where applicable, are as defined for the formula (I) or any applicable variations thereof.

In some embodiments, the compound of the formula (I-3) is a compound of the formula (I-3-e):

or a salt, prodrug or solvate thereof, wherein R³, R⁵ and R⁶ are as defined for the formula (I), (I-3), or any applicable variations thereof. In some particular embodiments of the compound of the formula (I-3-e), or a salt, prodrug or solvate thereof, wherein R⁶ is selected from the group consisting of:

and R¹, R³ and R⁵ are as specified in Table 2.

In one embodiment, provided is a compound of the formula (J):

or a salt, prodrug or solvate thereof, where X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as described for the formula (I), or any variations thereof. It is intended and understood that each and every variations of X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸, and each and every combinations thereof described herein for the formula (I) apply to the formula (J) as if each and every variations and combinations are individually described. For example, in some embodiments, provided is a compound of the formula (J), or a salt, prodrug or solvate thereof, where X¹ is N or CR¹¹ where R¹¹ is H, X² is O or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxy groups and R⁸ is hydrogen.

In one embodiment, the compound of the formula (J) is of the formula (J-1):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R⁷ are as defined for the formula (J) or formula (I) or any variations thereof. In some of these embodiments, R¹ is halo or unsubstituted or substituted C₁-C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁-C₁₀ alkyl, alkoxy, halo-substituted C₁-C₁₀ alkoxy, alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted or substituted C₁-C₁₀ alkyl; and R⁷ is hydrogen, unsubstituted or substituted C₁-C₁₀ alkyl, unsubstituted or substituted C₃-C₁₀ cycloalkyl, or unsubstituted or substituted C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl.

In some embodiments, provided is a compound of the formula (J-1), or a salt, prodrug or solvate thereof, wherein R¹ is halo (e.g., fluoro or chloro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R³ is halo (e.g., iodo or bromo), substituted C₁-C₁₀ alkyl (e.g., trifluoromethyl), halo-substituted C₁-C₁₀ alkoxy (e.g., trifluoromethoxy), C₁-C₁₀ alkylthio (e.g., methylthio), —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b). In some of these embodiments, R³ is —SO₂R^(a) where R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., SO₂Me). In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl (e.g., NMe₂). In some of these embodiments, R³ is —C(O)OR^(b) where R^(b) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., CO₂Me). In some of these embodiments, R⁵ is hydrogen, halo (e.g., fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group. In some of these embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₆ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some of these embodiments, R⁷ is unsubstituted or substituted C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In some of these embodiments, R⁷ is unsubstituted or substituted C₃-C₆ cycloalkyl C₁-C₆ alkyl. In some of these embodiments, R⁷ is unsubstituted or substituted C₃-C₄ cycloalkyl C₁-C₃ alkyl (e.g., cyclopropylmethyl). In some particular embodiments, the compound is of the formula (J-1), or a salt, prodrug or solvate thereof, wherein R¹ is fluoro or chloro, R³ is iodo or bromo, R⁵ is fluoro, and R⁷ is selected from the group consisting of cyclopropylmethyl, 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl. In some of these embodiments, R⁷ is selected from the group consisting of 2-hydroxyethyl, (R)-3-hydroxy-2-methylpropyl, (S)-3-hydroxy-2-methylpropyl, (R)-2,3-dihydroxypropyl, (S)-2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.

In one embodiment, the compound of the formula (J) is of the formula (J-2):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof.

In one embodiment, the compound of the formula (J) is of the formula (J-3):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof.

In some embodiments, provided is a compound of the formula (J-2) or (J-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo or unsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted or substituted C₁-C₁₀ alkyl; R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group; and R¹¹ is hydrogen.

In some embodiments, provided is a compound of the formula (J-2) or (J-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo (e.g., fluoro or chloro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R³ is halo (e.g., iodo or bromo), substituted C₁-C₁₀ alkyl (e.g., trifluoromethyl), halo-substituted C₁-C₁₀ alkoxy(e.g., trifluoromethoxy), C₁-C₁₀ alkylthio(e.g., methylthio), —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), or —C(O)OR^(b). In some of these embodiments, R³ is —SO₂R^(a) where R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., SO₂Me).

In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl (e.g., NMe₂). In some of these embodiments, R³ is —C(O)OR^(b) where R^(b) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., CO₂Me). In some of these embodiments, R⁵ is hydrogen, halo (e.g., fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In some of these embodiments, R⁷ is C₁-C₁₀ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₆ alkyl substituted with at least 1 to 3 hydroxy groups. In some of these embodiments, R⁷ is C₁-C₄ alkyl substituted with 1 or 2 hydroxy groups (e.g., 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl). In some particular embodiments, the compound is of the formula (J-2) or (J-3), or a salt, prodrug or solvate thereof, wherein R¹ is fluoro or chloro, R³ is iodo or bromo, R⁵ is fluoro, and R⁷ is selected from the group consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.

In one embodiment, the compound of the formula (J) is of the formula (J-4):

or a salt, prodrug or solvate thereof, wherein X¹, X², R¹ and R³ are as defined for the formula (J) or (I), or any variations thereof. In one variation, X¹ is N and X² is S. In another variation, X¹ is CH and X² is O. In yet another variation, X¹ is CH and X² is S. In some of these variations, R¹ is fluoro and R³ is iodo. In some of these variations, R¹ is chloro and R³ is bromo.

In another embodiment, the compound is of the formula (K):

or a salt, prodrug or solvate thereof, where X¹, X², R¹, R², R³, R⁴, R⁵ and R¹⁰ are as described for the formula (I), or any variations thereof. It is intended and understood that each and every variations of X¹, X², R², R³, R⁴, R⁵ and R¹⁰ and each and every combinations thereof described herein for the formula (I) apply to the formula (K) as if each and every variations and combinations are individually described. For example, in some embodiments, provided is a compound of the formula (K), or a salt, prodrug or solvate thereof, where X¹ is N or CR¹¹ where R¹¹ is H, X² is O or S, R¹ is halo (e.g., fluoro or chloro), R² is hydrogen, R³ is halo (e.g., iodo or bromo), R⁴ is hydrogen, R⁵ is fluoro, and R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl. In one variation, X¹ is N and X² is S. In another variation, X² is S and X¹ is CR¹¹ where R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl. In another variation, X² is O and X¹ is CR¹¹ where R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl.

In one embodiment, the compound of the formula (K) is of the formula (K-1):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵ and R¹⁰ are as defined for the formula (K), (I) or any variations thereof.

In one embodiment, the compound of the formula (K) is of the formula (K-2):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R¹⁰ and R¹¹ are as defined for the formula (K), (I) or any variations thereof.

In one embodiment, the compound of the formula (K) is of the formula (K-3):

or a salt, prodrug or solvate thereof, wherein R¹, R³, R⁵, R¹⁰ and R¹¹ are as defined for the formula (K), (I) or any variations thereof.

In some embodiments, provided is a compound of the formula (K-1), (K-2) or (K-3), or a salt, prodrug or solvate thereof, wherein R¹ is halo or unsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted or substituted C₁-C₁₀ alkyl; R¹⁰ is unsubstituted or substituted C₁-C₁₀ alkyl, unsubstituted or substituted C₃-C₁₀ cycloalkyl or unsubstituted or substituted C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and R¹¹ is hydrogen where present. In some of these embodiments, R¹ is halo (e.g., fluoro or chloro). In some of these embodiments, R³ is halo (e.g., iodo or bromo). In some of these embodiments, R³ is —SO₂R^(a) where R^(a) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., SO₂Me). In some of these embodiments, R³ is —N(R^(c))R^(d) where R^(c) and R^(d) are independently hydrogen or C₁-C₁₀ alkyl (e.g., NMe₂). In some of these embodiments, R³ is —C(O)OR^(b) where R^(b) is unsubstituted or substituted C₁-C₁₀ alkyl (e.g., CO₂Me). In some of these embodiments, R³ is SO₂Me or CO₂Me. In some of these embodiments, R⁵ is hydrogen, halo (e.g., fluoro) or C₁-C₁₀ alkyl (e.g., methyl). In one particular embodiment, R⁵ is fluoro. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with at least one hydroxy group. In some of these embodiments, R¹⁰ is C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl substituted with 1 or 2 hydroxy groups (e.g., 1-(2,3-dihydroxypropyl)cyclopropyl).

In some embodiments, provided is a compound of the formula (K-1), (K-2) or (K-3), or a salt, prodrug or solvate thereof, wherein R¹ is fluoro or chloro, R³ is iodo or bromo, R⁵ is fluoro, R¹⁰ is selected from the group consisting of cyclopropyl and 1-(2,3-dihydroxypropyl)cyclopropyl, and R¹¹ is hydrogen where present. In some of these embodiments, R¹ is fluoro R³ is iodo, R⁵ is fluoro, R¹⁰ is 1-(2,3-dihydroxypropyl)cyclopropyl and R¹¹ is absent for a compound of the formula (K-1) or is hydrogen for a compound of the formula (K-2) or (K-3).

Representative examples of compounds detailed herein, including intermediates and final compounds according to the invention are depicted in the Tables and Examples herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

Representative compounds of the invention are shown in Table 3. In some embodiments, the invention provides a compound of Table 3, in its free base form or as pharmaceutically acceptable salts, or a stereoisomer thereof

TABLE 3 Exemplary compounds Compound No. Structure Compound Name 1

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- (2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 2

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2- fluoro-4-iodophenyl)amino)benzo[d]oxazole- 6-carboxamide 3

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro- N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 4

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3- dihydroxypropoxy)-4-fluorobenzo[d]oxazole- 6-carboxamide 5

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]oxazol-6- yl)cyclopropanesulfonamide 6

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]oxazol-6-yl)-1- (2,3-dihydroxypropyl)cyclopropane-1- sulfonamide 7

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]oxazol-6- yl)cyclopropanesulfonamide 8

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]oxazol-6-yl)-1-(2,3- dihydroxypropyl)cyclopropane-1-sulfonamide 9

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- (2-hydroxyethoxy)benzo[d]thiazole-6- carboxamide 10

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2- fluoro-4-iodophenyl)amino)benzo[d]thiazole- 6-carboxamide 11

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro- N-(2-hydroxyethoxy)benzo[d]thiazole-6- carboxamide 12

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3- dihydroxypropoxy)-4-fluorobenzo[d]thiazole- 6-carboxamide 13

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d]thiazol-6- yl)cyclopropanesulfonamide 14

1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2- fluoro-4-iodophenyl)amino)benzo[d]thiazol-6- yl)cyclopropane-1-sulfonamide 15

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]thiazol-6- yl)cyclopropanesulfonamide 16

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d]thiazol-6-yl)-1-(2,3- dihydroxypropyl)cyclopropane-1-sulfonamide 17

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- (2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole- 6-carboxamide 18

N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2- fluoro-4- iodophenyl)amino)benzo[d][1,2,3]thiadiazole- 6-carboxamide 19

5-((4-bromo-2-chlorophenyl)amino)-4-fluoro- N-(2- hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6- carboxamide 20

5-((4-bromo-2-chlorophenyl)amino)-N-(2,3- dihydroxypropoxy)-4- fluorobenzo[d][1,2,3]thiadiazole-6- carboxamide 21

N-(4-fluoro-5-((2-fluoro-4- iodophenyl)amino)benzo[d][1,2,3]thiadiazol- 6-yl)cyclopropanesulfonamide 22

1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2- fluoro-4- iodophenyl)amino)benzo[d][1,2,3]thiadiazol- 6-yl)cyclopropane-1-sulfonamide 23

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d][1,2,3]thiadiazol-6- yl)cyclopropanesulfonamide 24

N-(5-((4-bromo-2-chlorophenyl)amino)-4- fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3- dihydroxypropyl)cyclopropane-1-sulfonamide 25

4-fluoro-5-((2-fluoro-4-bromophenyl)amino)- N-(2-hydroxyethoxy)benzo[d]oxazole-6- carboxamide 26

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2- hydroxyethoxy)benzo[d]oxazole-6- carboxamide 27

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2- hydroxyethoxy)benzo[d]oxazole-6- carboxamide 28

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2- hydroxyethoxy)benzo[d]oxazole-6- carboxamide 29

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]oxazole-6-carboxamide 30

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]oxazole-6-carboxamide 31

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]oxazole-6-carboxamide 32

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- cyclopropylmethyl-benzo[d]oxazole-6- carboxamide 33

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)- N-cyclopropylmethyl-benzo[d]oxazole-6- carboxamide 34

4-fluoro-5-((2-fluoro-4-bromophenyl)amino)- N-(2-hydroxyethoxy)benzo[d]thiazol-6- carboxamide 35

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2- hydroxyethoxy)benzo[d]thiazol-6- carboxamide 36

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2- hydroxyethoxy)benzo[d]thiazol-6- carboxamide 37

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2- hydroxyethoxy)benzo[d]thiazol-6- carboxamide 38

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]thiazol-6-carboxamide 39

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]thiazol-6-carboxamide 40

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d]thiazol-6-carboxamide 41

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- cyclopropylmethyl-benzo[d]thiazol-6- carboxamide 42

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)- N-cyclopropylmethyl-benzo[d]thiazol-6- carboxamide 43

5-((4-bromo-2-fluorophenyl)amino)-4-fluoro- N-(2- hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6- carboxamide 44

4-fluoro-5-((2-fluoro-4- trifluoromethylphenyl)amino)-N-(2- hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 45

4-fluoro-5-((2-fluoro-4- methylthiophenyl)amino)-N-(2- hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 46

5-((4-trifluoromethoxy-2- chlorophenyl)amino)-4-fluoro-N-(2- hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6- carboxamide 47

5-((2-fluoro-4-iodophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 48

5-((4-bromo-2-fluorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 49

5-((4-bromo-2-chlorophenyl)amino)-N-(1,3- dihydroxy-isopropoxy)-4- fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide 50

4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N- cyclopropylmethyl-benzo[d][1,2,3]thiadiazol- 6-carboxamide 51

4-fluoro-5-((4-bromo-2-chlorophenyl)amino)- N-cyclopropylmethyl- benzo[d][1,2,3]thiadiazol-6-carboxamide

Compounds detailed herein may be present as salts even if salts are not depicted and it is understood that the invention embraces all salts and solvates (e.g., hydrate) of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds of the invention are pharmaceutically acceptable salts.

It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

The compounds depicted herein may have more than one stereoisomer, and occur as racemates, racemic mixtures where one enantiomer may be enriched, individual diastereomers, and mixtures of stereoisomers. All stereoisomers, including enantiomers and diastereomers are embraced by the present invention. Stereoisomers may be separated by methods known in the art. Compositions comprising compounds detailed herein where stereoisomers may exist may contain one pure stereomer or more than one stereoisomer where the stereoisomers are present in equal amounts or where some of the stereoisomers are enriched relative to the others.

The present invention includes within its scope prodrugs of the compound, such as the compound of the formula (I), (J), (K), (A-I) or any variations thereof. In general, such prodrugs are functional derivatives of the compound, such as functional derivatives of the compound of the formula (I), (J), (K), (A-I) or any variations thereof, which are readily convertible in vivo into the required compound of the formula (I), (J), (K), (A-I) or any variations thereof. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Prodrugs: Challenges and Rewards”, ed. V. J. Stella et al, Springer, 2007. A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the “parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfuric ester, or reduction or oxidation of a susceptible functionality. In some embodiments, a prodrug for a compound containing a hydroxy group may be an ester formed with an appropriate acid, such as lactic acid, citric acid, ascorbic acid, and the like.

A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 30% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 3% or about 1% impurity.

In one aspect, provided are kits comprising a compound detailed herein, or a salt, prodrug or solvate thereof, and suitable packaging. In one embodiment, a kit further comprises instructions for use. In one aspect, a kit comprises a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, or a salt, prodrug or solvate thereof, and instructions for use of the compounds in the treatment or prevention of a disease or condition which can be ameliorated by inhibition of MEK in an individual in need thereof.

Articles of manufacture comprising a compound detailed herein, or a salt, prodrug or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule and the like.

Synthetic Methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

Common organic solvents can be used in the following synthesis schemes. Typical solvents include, but not limited to, aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, benzine, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), alcohols (such as methanol, ethanol, propan-1-ol, isopropanol, t-butanol, ethane-1,2-diol), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU and so on.

General Synthesis of Compounds of Formula (I)

The compound of the formula (I) where X¹ is N, X² is S, R⁶ is —C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 1, wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 1 are illustrated further by an exemplary synthesis of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide, according to the reactions outlined in Scheme 1.1.

Step 1.1.1

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent is added strong base (such as LDA, nBuLi, LiHDMS) under nitrogen atmosphere. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.). The reaction is kept stirring for some time (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. The resulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h) and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethyl ether and dioxane).

Step 1.1.2

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) under strong basic condition (such as LDA, n-BuLi, LiHDMS) in appropriate solvent. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.) and normally completes within several hours (3-12 h, prefer 5-10 h). 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethyl ether and dioxane).

Step 1.1.3

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl₂ in appropriate solvent. The reaction normally completes within several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer methanol and ethanol.

Step 1.1.4

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent is added base under nitrogen atmosphere, followed by Pd catalyst, phosphine ligand and phenylmethanethiol. The reaction is generally carried out at high temperature (80-130° C., prefer 90-110° C.) and normally complete within several hours (8-24 h, prefer 12-18 h). Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical bases include, but are not limited to, aliphatic and aromatic amine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and prefer N-ethyl-N-isopropylpropan-2-amine.

Typical Pd catalysts include, but are not limited to, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate and preferably select tris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to, dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1,1′-bis(diphenylphosphino)ferrocene and preferably select dimethylbisdiphenylphosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 1.1.5

Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate can be reacted with azide (such as NaN₃, KN₃) in appropriate solvent. The reaction is generally carried out at high temperature (60-120° C., prefer 80-100° C.) and normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-azido-5-(benzylthio)-3-fluoro fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 1.1.6

Methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni) in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol, propan-1-ol and water.

Step 1.1.7

Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate can be readily prepared by cyclization of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate in the presence of inorganic acid and alkali nitrite in the appropriate solvent.

Said inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

Said alkali nitrite includes, but is not limited to, sodium nitrite, potassium nitrite and cesium nitrite.

Typical solvents are as defined above and prefer organic acid such as, but not limited to acetic acid and formic acid.

Step 1.1.8

Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid at ambient temperature in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate is obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, and acetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 1.1.9

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid can be prepared from methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate be deprotection in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF, MeOH and DMF.

Step 1.1.10

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide is obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU and TBTU.

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide.

Step 1.1.11

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide can be reacted under acidic condition in appropriate solvent. The reaction normally completes within (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide is obtained after conventional workup.

Typical acids include, but are not limited to, hydrochloric acid, sulfuric acid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and 1,2-dichloroethane.

A compound of the formula (I-1-a), i.e., a compound of the formula (I) where X¹ is N, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo may be synthesized according to Scheme X-1, wherein R¹, R², R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof; each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X is fluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-1-a) can be prepared from the reaction of the compound of formula (X-II) with hydroxylamine (R⁷OR⁸NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), 0-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (X-II) can be prepared from deprotection of the compound of formula (X-III) in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF according to different R¹⁴.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF, MeOH and DMF.

Step 3:

The compound of formula (X-III) where R³ is halo can be prepared from halogenation of the compound of formula (X-IV) in the presence of halogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS, MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, and acetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 4:

The compound of formula (X-IV) can be prepared from cyclization of the compound of formula (X-V) in the presence of diazotization reagents (such as inorganic acid and alkali nitrite) in appropriate solvent.

Typical inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

Typical alkali nitrite includes, but is not limited to, sodium nitrite, potassium nitrite and cesium nitrite.

Typical solvents are as defined above and prefer organic acid such as, but not limited to acetic acid and formic acid.

Step 5:

The compound of formula (X-V) can be prepared from reduction of the compound of formula (X-VI) in the presence of reduction reagents in appropriate solvent.

Typical reduction reagents include, but are not limited to hydrogenation catalyst, SnCl₂, PPh₃, NaBH₄, BH₃ and Raney Ni.

Typical solvents are as defined above and prefer methanol, ethanol, ethyl acetate and THF.

Step 6:

The compound of formula (X-VI) can be prepared from reaction of the compound of formula (X-VII) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ and KN₃

Typical solvents are as defined above and prefer DMSO, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 7:

The compound of formula (X-VII) can be prepared from the reaction of the compound of formula (X-VIII) with mercaptan (R¹⁵SH) in the presence of base, phosphine ligand and catalyst in appropriate solvent.

Typical bases include, but are not limited to, aliphatic and aromatic amine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and prefer N-ethyl-N-isopropylpropan-2-amine.

Typical catalysts prefer Pd catalysts, such as, but are not limited to, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate and preferably select tris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to, dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1,1′-bis(diphenylphosphino)ferrocene and preferably select dimethylbisdiphenylphosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 8:

The compound of formula (X-VIII) can be prepared from the reaction of the compound of formula (X-IX) with alcohol (R¹⁴OH) or halide (R¹⁴X) in the presence of optional catalyst in appropriate solvent.

Typical catalysts are selected according to different substrates and include SOCl₂, sulfuric acid, inorganic base (such as NaHCO₃, KHCO₃, Na₂CO₃) and organic base (such as triethylamine and N-ethyl-N-isopropylpropan-2-amine).

Typical solvents are as defined above and prefer methanol, ethanol, THF and DMF.

Step 9:

The compound of formula (X-IX) can be prepared from the reaction of the compound of formula (X-X) with the following compound in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 10:

The compound of formula (X-X) can be prepared from the reaction of the compound of formula (X-XI) with CO₂ in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

A compound of the formula (I-1-a) where R³ is other than halo may be synthesized according to Scheme X-2, where R¹, R², R⁴, R⁸, R⁵, R⁷ and are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The synthetic scheme (X-2) for formula (I-1-a) compound wherein R³ is other than halo is similar to the Scheme (X-1) for formula (I-1-a) wherein R³ is halo. The difference between the two schemes is that the following aniline is used in the synthetic scheme (X-2) and the corresponding Step 3 is omitted.

The compound of formula (I-1-b), where R¹, R², X³, X⁴, X⁵, X⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-1-b) can be prepared from the reaction of the compound of formula (X-II) with alcohol (R⁷OH) in the presence of coupling reagents or with halide (R⁷X) in the presence of base in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-1-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-1-c) can be prepared from the reaction of the compound of formula (X-II) with amine (R⁸R⁷NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-1-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-1-d) can be prepared from the compound of formula (X-XII) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine, pyridine and potassium trimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF.

Step 2:

The compound of formula (XII) can be prepared from the reaction of the compound of formula (XIII) with R⁷SO₂X (wherein X is fluoro, chloro, bromo and iodo) in the presence of base and catalyst in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical catalysts include, but are not limited to 4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane and chloroform.

Step 3:

The compound of formula (X-XIII) can be prepared from the reaction of the compound of formula (X-II) with azide in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethyl carbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸ wherein each of R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl and C₆-C₁₀ aryl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si, Ph₃Si, Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl or C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is CR¹¹, X² is O, R⁶ is —C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 2, wherein R¹, R², R⁴, R⁵, R⁷, and R¹¹ are as defined for the formula (J), (I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and each R¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 2 are illustrated further by an exemplary synthesis of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]oxazole-6-carboxamide, according to the reactions outlined in Scheme 2.1.

Step 2.1.1

2,3,4-Trifluorophenol can be protected with hydroxy protection reagent (such as BnBr, BnCl) in the presence of base in appropriate inert solvent. The reaction generally is carried out at ambient temperature and normally completes within several hours (3-12 h, prefer 5-10 h). 1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventional workup.

Typical bases include Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuOK and t-BuONa.

Typical solvents are as defined above and prefer acetone and methyl ethyl ketone.

Step 2.1.2

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inert solvent is added strong base (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The stirring is maintained at this temperature for several hours (0.5-12 h, prefer 0.5-2 h). The mixture is transferred to a bottle with dry ice and the resulting mixture is stirred for some time (such as 3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer tetrahydrofuran.

Step 2.1.3

5-Benzoxy-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) in the presence of strong base (such as LDA, n-BuLi, LiHDMS). The reaction generally is carried out at low temperature (−50° C.-−80° C., prefer −78° C.) and normally completes within several hours (3-12 h, prefer 5-10 h). 5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.

Step 2.1.4

5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be protected by protection reagent of acid or hydroxyl (such as BnBr, BnCl) under basic condition in appropriate inert solvent The reaction normally complete within several hours (3-12 h, prefer 5-10 h). Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, tBuOK, and tBuONa.

Typical solvents are as defined above and prefer acetone and methyl ethyl ketone.

Step 2.1.5

Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate can be reacted with azide (such as NaN₃, KN₃) in appropriate solvent. The reaction generally is carried out at high temperature (60-120° C., prefer 80-100° C.) and normally completes within several hours (1-12 h, prefer 3-10 h). The desired product is obtained after conventional workup.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 2.1.6

Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni). The reaction normally completes within several hours (1-12 h, prefer 3-10 h). 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol, propan-1-ol and water.

Step 2.1.7

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid can be cyclized by trialkoxymethane in the presence of acid in appropriate solvent. The reaction normally completes within several hours (0.2-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro phenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.

Said trialkoxymethane includes, but are not limited to, trimethoxymethane and triethoxymethane.

Typical acids include p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, formic acid, acetic acid and sulfuric acid.

Typical solvents are as defined above and prefer methyl acetate, ethyl acetate and trimethoxymethane.

Step 2.1.8

4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with halogenations reagent (such as NIS) under acidic condition in appropriate solvent. The reaction generally is carried out at ambient temperature and normally completes within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid and acetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 2.1.9

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU and TBTU.

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide.

Step 2.1.10

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide can be reacted under acidic condition in appropriate solvent. The reaction normally completes within (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.

Typical acids include, but not limited to, hydrochloric acid, sulfuric acid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and 1,2-dichloroethane.

A compound of the formula (I-2-a), i.e., a compound of the formula (I) where X¹ is CR¹¹, X² is O and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo may be synthesized according to Scheme Y-1, wherein R¹, R², R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof; each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X is fluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-2-a) can be prepared from the reaction of the compound of formula (Y-II) with hydroxylamine (R⁷OR⁸NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (Y-II) where R³ is halo can be prepared from halogenation of the compound of formula (Y-III) in the presence of halogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS, MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, and acetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 3:

The compound of formula (Y-III) where R¹¹ is hydrogen can be prepared from cyclization of the compound of formula (Y-IV) in the presence of acid and tri(C₁-C₆ alkyl)orthoformate in appropriate solvent.

Typical acids include, but are not limited to p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, methane sulfonic acid and benzenesulfonic acid.

Said tri(C₁-C₆ alkyl)orthoformate includes trimethoxymethane and triethoxymethane.

Typical solvents are as defined above and prefer MeOH, CH₂Cl₂, CHCl₃, DMSO and N,N-dimethylformamide.

The compound of formula (Y-III) where R¹¹ is other than hydrogen can be prepared from the reaction of the compound of formula (Y-IV) with substituted acid (R¹¹COOH) in the presence of catalyst in appropriate solvent.

Typical catalyst includes, but is not limited to polyphosphoric acids.

Step 4:

The compound of formula (Y-IV) can be prepared from hydrogenation of the compound of formula (Y-V) in the presence of catalyst in appropriate solvent.

Typical hydrogenation catalysts include, but are not limited to Pd/C, Pt and Ni.

Typical solvents are as defined above and prefer methanol, ethanol and THF.

Step 5:

The compound of formula (Y-V) can be prepared from reaction of the compound of formula (Y-VI) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ and KN₃

Typical solvents are as defined above and prefer DMSO, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 6:

The compound of formula (Y-VI) can be prepared from the reaction of the compound of formula (Y-VII) with alcohol (R¹³OH) or halide (R¹³X, X prefers Br) in the presence of acid or base in appropriate solvent.

Where the compound of formula (Y-VII) is reacted with alcohol (R¹³OH), typical acids include, but are not limited to, sulfuric acid, p-toluenesulfonic acid, pyridinium toluene-4-sulphonate and trifluoroacetic acid.

Typical solvents are as defined above and prefer benzyl alcohol, methanol, ethanol, 1-propanol and n-butanol.

Where the compound of formula (Y-VII) is reacted with halide (R¹³X), typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuONa and t-BuOK.

Typical solvents are as defined above and prefer N,N-dimethylformamide, N,N-dimethylacetamide.

Step 7:

The compound of formula (Y-VII) can be prepared from the reaction of the compound of formula (Y-VIII) with the following compound in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 8:

The compound of formula (Y-VIII) can be prepared from the reaction of the compound of formula (Y-IX) with CO₂ in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 9:

The compound of formula (Y-IX) can be prepared from the reaction of the compound of formula (Y-X) with R¹²X (X prefers bromo) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuONa and t-BuOK.

Typical solvents are as defined above and prefer THF, DMF and acetone.

A compound of the formula (I-2-a), i.e., a compound of the formula (I) where X¹ is CR¹¹, X² is O and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is other than halo may be synthesized according to Scheme Y-2, wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The synthetic scheme (Y-2) for compound of the formula (I-2-a) wherein R³ is other than halo is similar to the scheme (Y-1) for formula (I-2-a) wherein R³ is halo. The difference between the two schemes is that the following aniline is used in the synthetic scheme (A-2) and the corresponding Step 2 is omitted.

The compound of formula (I-2-b), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-2-b) can be prepared from the reaction of the compound of formula (Y-II) with alcohol (R⁷OH) in the presence of coupling reagents or with halide (R⁷X) in the presence of base in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-2-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-2-c) can be prepared from the reaction of the compound of formula (Y-II) with amine (R⁸R⁷NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-2-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-2-d) can be prepared from the compound of formula (Y-XI) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine, pyridine and potassium trimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF and CH₂Cl₂.

Step 2:

The compound of formula (Y-XI) can be prepared from the reaction of the compound of formula (Y-XII) with R⁷SO₂X (wherein X is fluoro, chloro, bromo and iodo) in the presence of base and catalyst in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical catalysts include, but are not limited to 4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane and chloroform.

Step 3:

The compound of formula (Y-XII) can be prepared from the reaction of the compound of formula (Y-II) with azide in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethyl carbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸, wherein each of e, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl and C₆-C₁₀ aryl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si, Ph₃Si, Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl or C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is CR¹¹, X² is R⁶, is —C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 3, wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and each R¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 3 are illustrated further by an exemplary synthesis of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]thiazole-6-carboxamide, according to the reactions outlined in Scheme 3.1.

Step 3.1.1

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent is added strong base (such as LDA, nBuLi, LiHDMS) under nitrogen atmosphere. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.). The reaction is kept stirring for some time (0.5-12 h, preferably select 0.5-2 h) and is added dry ice. The resulting mixture is kept stirring for some time (3-12 h, prefer 5-10 h) and 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethyl ether and dioxane).

Step 3.1.2

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) under strong basic condition (such as LDA, n-BuLi, LiHDMS) in appropriate solvent. The reaction is generally carried out at low temperature (−50-−80° C., prefer −78° C.) and normally completes within several hours (3-12 h, prefer 5-10 h). 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.

Typical solvents are as defined above and prefer anhydrous THF, ethyl ether and dioxane).

Step 3.1.3

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl₂ in appropriate solvent. The reaction normally completes within several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer methanol and ethanol.

Step 3.1.4

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent is added base under nitrogen atmosphere, followed by Pd catalyst, phosphine ligand and (4-methoxyphenyl)methanethiol. The reaction is generally carried out at high temperature (80-130° C., prefer 90-110° C.) and normally complete within several hours (8-24 h, prefer 12-18 h). Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Typical bases include, but are not limited to, aliphatic and aromatic amine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa, ^(t)BuOK) and prefer N-ethyl-N-isopropylpropan-2-amine.

Typical Pd catalysts include, but are not limited to, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate and preferably select tris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to, dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1,1′-bis(diphenylphosphino)ferrocene and preferably select dimethylbisdiphenyl phosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 3.1.5

Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be reacted with azide (such as NaN₃, KN₃) in appropriate solvent. The reaction is generally carried out at high temperature (60-120° C., prefer 80-100° C.) and normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 3.1.6

Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni) in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Typical solvents are as defined above and prefer methanol, ethanol, propan-1-ol and water.

Step 3.1.7

5,5′-Disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate) can be prepared from methyl 4-amino-3-fluoro-2-((2-fluoro phenyl)amino)-5-((4-methoxybenzyl)thio)benzoate by deprotection in appropriate solvent. The desired product is obtained after conventional workup.

Typical deprotection reagents may be acid, Pd/C, Lewis acid or R₄NF according to R¹⁵.

Said acid includes, but are not limited to, CF₃COOH.

Said Lewis acid includes, but is not limited to, BF₃ and BBr₃.

Said deprotection reagents include oxidative reagents such as, but are not limited to, ammonium ceric nitrate and DDQ and prefer DDQ.

Typical solvents are as defined above and prefer dichloromethane, chloroform, MeOH and EtOH.

Step 3.1.8

5,5′-Disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate) can be reduced in appropriate solvent. Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate is obtained after conventional workup.

Said reductive reagents include NaBH₄, NaCNBH₃, NaBH(OAc)₃, Zn powder and Fe powder.

Typical solvents are as defined above and prefer the mixture of THF and MeOH.

Step 3.1.9

Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercapto benzoate can be cyclized in the presence of acid in appropriate solvent. The reaction normally completes within several hours (0.2-12 h, prefer 0.5-10 h). Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.

Typical acids include, but are not limited to p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, formic acid, acetic acid and sulfuric acid.

Typical solvents are as defined above and prefer methyl acetate, ethyl acetate and trimethoxymethane.

Step 3.1.10

Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid at ambient temperature in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, and acetic acid.

Typical solvents are as defined above and prefer N,N-dimethylformamide and N,N-dimethylacetamide.

Step 3.1.11

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be prepared from methyl 4-fluoro-5-((2-fluoro-4-iodo phenyl)amino)benzo[d]thiazole-6-carboxylate be deprotection in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃ and K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF, MeOH and DMF.

Step 3.1.12

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.

Coupling reagents include, but are not limited to, HOBt, EDCI, HATU and TBTU.

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide.

Step 3.1.13

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide can be reacted under acidic condition in appropriate solvent. The reaction normally completes within (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.

Typical acids include, but not limited to, hydrochloric acid, sulfuric acid and trifluoroacetic acid.

Typical solvents are as defined above and prefer dichloromethane and 1,2-dichloroethane.

A compound of the formula (I-3-a), i.e., a compound of the formula (I) where X¹ is CR¹¹, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is halo may be synthesized according to Scheme Z-1, wherein R¹, R², R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof; each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl, and X is fluoro, chloro, bromo or iodo.

Step 1:

The compound of formula (I-3-a) can be prepared from the reaction of the compound of formula (Z-II) with hydroxylamine (R⁷OR⁸NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, 1,2-dichloroethane, THF and N,N-dimethylformamide.

Step 2:

The compound of formula (Z-II) can be prepared from deprotection of the compound of formula (Z-III) in appropriate solvent.

Typical deprotection reagents may be base, Pd/C, Lewis acid or R₄NF according to different R¹⁴.

Said base includes, but are not limited to, NaOH, KOH, Na₂CO₃, K₂CO₃.

Said Lewis acids include, but are not limited to AlCl₃, BF₃ and BBr₃.

Typical solvents are as defined above and prefer dichloromethane, THF, MeOH and DMF.

Step 3:

The compound of formula (Z-III) where R³ is halo can be prepared from halogenation of the compound of formula (Z-IV) in the presence of halogenation reagents and acid in appropriate solvent.

Typical halogenation reagents include, but are not limited to NCS, NBS, MS and so on.

Typical acids include, but are not limited to, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, and acetic acid.

Typical solvents are as defined above and prefer CH₂Cl₂, CHCl₃, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 4:

The compound of formula (Z-IV) where R¹¹ is hydrogen can be prepared from cyclization of the compound of formula (Z-V) in the presence of acid and tri(C₁-C₆ alkyl)orthoformate in appropriate solvent.

Typical acids include, but are not limited to p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, methane sulfonic acid and benzenesulfonic acid.

Said tri(C₁-C₆ alkyl)orthoformate includes trimethoxymethane and triethoxymethane.

Typical solvents are as defined above and prefer MeOH, CH₂Cl₂, CHCl₃, DMSO and N,N-dimethylformamide.

The compound of formula (Z-IV) where R¹¹ is other than hydrogen can be prepared from the reaction of the compound of formula (Z-V) with substituted acid (R¹¹COOH), R¹¹C(OMe)₃ or R¹¹C(OEt)₃ in the presence of catalyst in appropriate solvent.

Typical catalyst includes, but is not limited to polyphosphoric acids.

Step 5:

The compound of formula (Z-V) can be prepared from the compound of formula (Z-VI) in the presence of reduction reagent in appropriate solvent.

Typical reduction reagents include, but are not limited to NaBH₄, NaBH₃CN, NaBH(Ac)₃, Zn powder and Fe powder.

Typical solvents are as defined above and prefer the mixture of THF and MeOH.

Step 6:

The compound of formula (Z-VI) can be prepared from the compound of formula (Z-VII) in the presence of deprotection reagent in appropriate solvent.

Typical deprotection reagents may be acid, Pd/C, Lewis acid or R₄NF according to R¹⁵.

Said acid includes, but are not limited to, CF₃COOH.

Said Lewis acid includes, but is not limited to, BF₃ and BBr₃.

Said deprotection reagents include oxidative reagents such as, but are not limited to, ammonium ceric nitrate and DDQ and prefer DDQ.

Typical solvents are as defined above and prefer dichloromethane, chloroform, MeOH and EtOH.

Step 7:

The compound of formula (Z-VII) can be prepared from reduction of the compound of formula (Z-VIII) in the presence of reduction reagents in appropriate solvent.

Typical reduction reagents include, but are not limited to hydrogenation catalyst, SnCl₂, PPh₃, NaBH₄, BH₃ and Raney Ni.

Typical solvents are as defined above and prefer methanol, ethanol, ethyl acetate and THF.

Step 8:

The compound of formula (Z-VIII) can be prepared from reaction of the compound of formula (Z-IX) with azide in appropriate solvent.

Typical azides prefer alkali azide, such as but not limited to NaN₃ and KN₃

Typical solvents are as defined above and prefer DMSO, N,N-dimethylformamide and N,N-dimethylacetamide.

Step 9:

The compound of formula (Z-IX) can be prepared from the reaction of the compound of formula (Z-X) with mercaptan (R¹⁵SH) in the presence of base, phosphine ligand and catalyst in appropriate solvent.

Typical bases include, but are not limited to, aliphatic and aromatic amine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuOK) and prefer N-ethyl-N-isopropylpropan-2-amine.

Typical catalysts prefer Pd catalysts, such as, but are not limited to, tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate and preferably select tris(dibenzylideneacetone)dipalladium.

Typical phosphine ligands include, but are not limited to, dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1,1′-bis(diphenylphosphino)ferrocene and preferably select dimethylbisdiphenyl phosphinoxanthene.

Typical solvents are as defined above and prefer dioxane.

Step 10:

The compound of formula (Z-X) can be prepared from the reaction of the compound of formula (Z-XI) with alcohol (R¹⁴OH) or halide (R¹⁴X) in the presence of optional catalyst in appropriate solvent.

Typical catalysts are selected according to different substrates and include SOCl₂, sulfuric acid, inorganic base (such as NaHCO₃, KHCO₃, Na₂CO₃) and organic base (such as triethylamine and N-ethyl-N-isopropylpropan-2-amine).

Typical solvents are as defined above and prefer methanol and ethanol.

Step 11:

The compound of formula (Z-XI) can be prepared from the reaction of the compound of formula (Z-XII) with the following compound in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

Step 12:

The compound of formula (Z-XII) can be prepared from the reaction of the compound of formula (Z-XIII) with CO₂ in the presence of strong base in appropriate solvent.

Typical strong base include, but are not limited to LDA, n-BuLi and LiHDMS.

Typical solvents are as defined above and prefer anhydrous THF.

A compound of the formula (I-3-a), i.e., a compound of the formula (I) where X¹ is CR¹¹, X² is S and R⁶ is —C(O)N(R⁸)OR⁷, where R³ is other than halo may be synthesized according to Scheme Z-2, wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The synthetic scheme (Z-2) of formula (I-3-a) compound wherein R³ is other than halo is similar to the scheme (Z-1) of formula (I-1) wherein R³ is halo. The difference between the two schemes is that the following aniline is used in the synthetic scheme (Z-2) and the corresponding Step 3 is omitted.

The compound of formula (I-3-b), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-3-b) can be prepared from the reaction of the compound of formula (Z-II) with alcohol (R⁷OH) in the presence of coupling reagents or with halide (R⁷X) in the presence of base in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-3-c), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

The compound of formula (I-3-c) can be prepared from the reaction of the compound of formula (Z-II) with amine (R⁸R⁷NH) in the presence of coupling reagents in appropriate solvent.

Typical coupling reagents include, but are not limited to 1-Hydroxy-1H-benzotriazole (HOBt), 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (EDCI), O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU) and O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).

Typical solvents are as defined above and prefer dichloromethane, chloroform and THF.

The compound of formula (I-3-d), where R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, is prepared according to the method outlined in the following scheme:

Step 1:

The compound of formula (I-3-d) can be prepared from the compound of formula (Z-XIV) in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine, pyridine and potassium trimethylsilanolate) and prefer potassium trimethylsilanolate.

Typical solvents are as defined above and prefer THF.

Step 2:

The compound of formula (Z-XIV) can be prepared from the reaction of the compound of formula (Z-XV) with R⁷SO₂X (wherein X is fluoro, chloro, bromo and iodo) in the presence of base and catalyst in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical catalysts include, but are not limited to 4-dimethylaminopyridine (DMAP).

Typical solvents are as defined above and prefer dichloromethane and chloroform.

Step 3:

The compound of formula (Z-XV) can be prepared from the reaction of the compound of formula (Z-II) with azide in the presence of base in appropriate solvent.

Typical bases include, but are not limited to, inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, ^(t)BuONa and ^(t)BuOK) and organic base (such as diethylamine, triethylamine and pyridine) and prefer triethylamine.

Typical azides include diphenyl phosphoryl azide (DPPA) and ethyl carbonochloridate/NaN₃ and prefer diphenyl phosphoryl azide (DPPA).

Typical solvents are as defined above and prefer t-BuOH.

In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1-3 methoxy, C₁-C₄ alkyl or —SiR¹⁶R¹⁷R¹⁸, wherein each of R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₆ alkyl and C₆-C₁₀ aryl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, t-BuMe₂Si, Ph₃Si, Et₃Si, n-Pr₃Si or i-Pr₃Si. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl or C₁-C₂ alkyl. In some embodiments, each R¹⁴ and R¹⁵ is independently benzyl, p-methoxybenzyl or methyl.

The compound of the formula (I) where X¹ is N, X² is O, R⁶ is —C(O)NHOR⁷, and R³ is halo can be synthesized according to Scheme 4, wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) or any variations thereof; and each R¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

The steps in Scheme 4 are illustrated further by an exemplary synthesis of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d][1,2,3]oxadiazole-6-carboxamide, according to the reactions outlined in Scheme 4.1.

Thus, in one aspect, the invention provides methods and processes for making a compound of the formula (J), or a salt thereof, comprising coupling of a compound of the formula (G), or a salt thereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a salt thereof:

wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J), or a salt thereof, wherein X¹ is N and X² is S, comprising coupling of a compound of the formula (G-1a), or a salt thereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined for the formula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method further comprises converting a compound of the formula (F-1a) or a salt thereof to the compound of the formula (G-1a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method further comprises diazotization of the compound of the formula (F-1a) or a salt thereof.

In some embodiments, provided is a method of making a compound of the formula (J), or a salt thereof, wherein, X¹ is CR¹¹ and X² is O, comprising coupling of a compound of the formula (G-2a), or a salt thereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are as defined for the formula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method further comprises converting a compound of the formula (F-2a) or a salt thereof to the compound of the formula (G-2a) or a salt thereof:

In some embodiments of the method where R¹¹ is hydrogen, the method comprises contacting an orthoester of formic acid with the compound of the formula (F-2a) or a salt thereof.

In some embodiments, provided is a method of making a compound of the formula (J), or a salt thereof, wherein X¹ is CR¹¹ and X² is S, comprising coupling of a compound of the formula (G-3a), or a salt thereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are as defined for the formula (J), (I) or any variations thereof, and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹¹, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In some embodiments, the method further comprises converting a compound of the formula (F-3a) or a salt thereof to the compound of the formula (G-3a) or a salt thereof:

In some embodiments, the method further comprises converting a compound of the formula (F-1a) or a salt thereof to the compound of the formula (F-3a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl. In one variation of the method, the compound of the formula (F-1a) or a salt thereof is converted to the compound of the formula (F-3a) or a salt thereof via an intermediate of the formula (F-3a′) or a salt thereof:

In some of these embodiments of the method where R¹¹ is hydrogen, the method comprises reacting an orthoester of formic acid with a compound of the formula (F-3a) or a salt thereof.

In some embodiments, provided is a method of making a compound of the formula (J-1a), or a salt thereof, comprising the steps according to Scheme 1A:

wherein R¹, R², R³, R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) or any variations thereof, provided that R³ is other than halo; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-1a) where R³ is halo, or a salt thereof, comprising the steps according to Scheme 1B:

wherein R¹, R², R⁴, R⁵ and R⁷ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-2a) or a salt thereof, comprising the steps according to Scheme 2A:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof, provided that R³ is other than halo; R¹⁴ is hydrogen, allyl or R¹³; and each R¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-2a), where R³ is halo, or a salt thereof, comprising the steps according to Scheme 2B:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof; R¹⁴ is hydrogen, allyl or R¹³; and each R¹² and R¹³ is independently benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-3a) or a salt thereof, comprising the steps according to Scheme 3A:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof, provided that R³ is other than halo; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-3a) or a salt thereof, comprising the steps according to Scheme 3A-1:

wherein R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof, provided that R³ is other than halo; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-3a) where R³ is halo, or a salt thereof, comprising the steps according to Scheme 3B:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some embodiments, provided is a method of making a compound of the formula (J-3a) where R³ is halo, or a salt thereof, comprising the steps according to Scheme 3B-1:

wherein R¹, R², R⁴, R⁵, R⁷ and R¹¹ are as defined for the formula (J), (I) or any variations thereof; and each R¹⁴ and R¹⁵ is independently allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

Further Embodiments of the Invention

In one aspect, provided herein is a compound of formula (A-I), or a pharmaceutically accepted salt, prodrug or solvate thereof:

wherein:

each of R¹, R², R⁴ and R⁵ is independently H, halogen, nitro, azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁶, —OC(O)R⁷—SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)alkyl, —S(O)_(j)(C₁-C₁₀ alkyl), —S(O)_(j)(CR⁸R⁹)_(m), C₆-C₁₄ aryl, C₆-C₁₄ arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR⁸R⁹)_(m)-aryl, —NR⁸(CR⁸R⁹)_(m)-aryl, —O(CR⁸R⁹)_(m)-heteroaryl, —NR⁸(CR⁸R⁹)_(m)-heteroaryl, —O(CR⁸R⁹)_(m)-heterocyclyl, or —NR⁸(CR⁸R⁹)_(m)-heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, heteroaryl(C₁-C₁₀ alkyl), heterocycloalkyl, and heterocycloalkyl(C₁-C₁₀ alkyl);

R³ is H, halogen, cyano, nitro, azido, —OR⁷, —SR′, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, —S(O)_(j)(C₁-C₁₀ alkyl), —S(O)_(j)(CR⁸R⁹)_(m)C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl, (heterocycloalkyl)C₁-C₁₀ alkyl, —O(CR⁸R⁹)_(m)-aryl, —NR⁸(CR⁸R⁹)_(m)-aryl, —O(CR⁸R⁹)_(m)-heteroaryl, —NR⁸(CR⁸R⁹)_(m)-heteroaryl, —O(CR⁸R⁹)_(m)— heterocyclyl, or —NR⁸(CR⁸R⁹)_(m)-heterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl portions is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁰, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, heteroaryl(C₁-C₁₀ alkyl), heterocycloalkyl, and heterocycloalkyl(C₁-C₁₀ alkyl);

R⁶ is heteroaryl, heterocycloalkyl, —C(O)OR⁷, —C(O)NR⁷R⁸, —C(O)NR⁸OR⁷, —C(O)R⁸OR⁷, —C(O)(C₃-C₁₀ cycloalkyl), —C(O)(C₁-C₁₀ alkyl), —C(O)(C₆-C₁₄ aryl), —C(O)heteroaryl or —C(O)heterocycloalkyl; wherein each group above is optionally substituted with one or more substituents independently selected from —NR⁷R⁸, —OR⁷, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, wherein each group is optionally substituted with 1 or 2 substituents independently selected from —NR⁷R⁸ and —OR⁷;

each of R⁷, R⁸ and R⁹ is independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl portions is optionally substituted with one or more groups independently selected from hydroxyl, oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁷ and R⁸, together with the atom to which they are attached, form a substituted or unsubstituted 3- to 10-member ring; wherein each group is optionally substituted with one or more substituents independently selected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁸ and R⁹, together with the atom to which they are attached, form a substituted or unsubstituted 3- to 10-member ring; wherein each group is optionally substituted with one or more substituents independently selected from H, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R¹⁰ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R′ and R′″ are independently H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

or

any two of R′, R″, R′″ and R″″, together with the atom to which they are attached, form a 4- to 10-membered heteroaryl or heterocyclic ring, wherein each heteroaryl and heterocyclic rings is optionally substituted with one or more groups independently selected from H, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

X¹ is CR¹¹ or N;

R¹¹ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl, (C₁-C₁₀ alkyl)₃silyl, (C₁-C₁₀ alkyl)₂(C₆-C₁₄ aryl)silyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

X² is O, S or —C(═O);

m is 0, 1, 2, 3, 4 or 5; and

j is 0, 1 or 2.

In some embodiments, the compound of the formula (A-I), where X¹ is —CR¹¹, having the formula (A-I-1), or where X¹ is N, having the formula (A-I-2):

In some embodiments, the compound of the formula (A-I) where X¹ is —CR¹¹ and X² is O, S, or —C(═O) having the formula (A-I-1-a), (A-I-1-b) or (A-I-1-c) respectively:

In some embodiments, the compound of the formula (A-I) where X¹ is N and X² is O, S, or —C(═O) having the formula (A-I-2-a), (A-I-2-b) or (A-I-2-c) respectively:

Also provided are methods of making compounds of the formula (A-I) and salts, prodrugs and solvates thereof. For example, a compound of the formula (A-I-1-a), (A-I-1-b), (A-I-2-a) or (A-I-2-b) may be prepared, according to Schemes A-1, A-2, A-3 or A-4 respectively:

wherein R¹, R², R³, R⁴, R⁵ and R¹¹ are as described for the formula (A-I), and

R⁷ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

-   -   R′, R″ and R′″ are independently hydrogen, C₁-C₁₀ alkyl, C₂-C₆         alkenyl, C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;     -   R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄         aryl)C₁-C₁₀ alkyl;     -   or     -   any two of R′, R″, R′″ and R″″, together with the atom to which         they are attached, form a 4- to 10-member heteroaryl or         heterocyclic ring, wherein said heteroaryl and heterocyclic         rings are optionally substituted with one or more groups         independently selected from halogen, cyano, nitro,         trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,         C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl,         (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and         (heterocycloalkyl)C₁-C₁₀ alkyl;

each of R¹², R¹³, R¹⁴ and R¹⁵ is independently benzyl, benzyl substituted with 1 to 3 methoxy, C₁-C₅ alkyl and —SiR¹⁶R¹⁷R¹⁸, wherein each of R¹⁶, R¹⁷ and R¹⁸ is independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.

In some preferred embodiments, the compound is of the formula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as described as below with various degrees of preferences:

Preferred X¹ is CR¹¹ or N;

More preferred X¹ is CR¹¹ or N;

Especially preferred X¹ is CR¹¹ or N;

Particularly preferred X¹ is CR¹¹ or N.

Preferred R¹¹ is H, C₁-C₆ alkyl or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

More preferred R¹¹ is H, C₁-C₄ alkyl or (C₃-C₆ cycloalkyl)C₁-C₄ alkyl;

Especially preferred R¹¹ is H or C₁-C₄ alkyl;

Particularly preferred R¹¹ is H.

Preferred R¹, R², R⁴ and R⁵ are each independently H, halogen, C₁-C₁₀ alkyl, wherein C₁-C₁₀ alkyl is optionally substituted with one or more substituents independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —OR⁷, —C(O)R⁷, —C(O)OR⁷, —NR⁸C(O)OR¹⁰, —OC(O)R⁷, —NR⁸SO₂R¹⁶, —SO₂NR⁷R⁸, —NR⁸C(O)R⁷, —C(O)NR⁷R⁸, —NR⁹C(O)NR⁷R⁸, —NR⁹C(NCN)NR⁷R⁸, —NR⁷R⁸, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

More preferred R¹ is H, halogen, C₁-C₆ alkyl, halogenated C₁-C₆ alkyl, halogenated C₁-C₆ alkoxy, or halogenated alkylsulphanyl;

Especially preferred R¹ is H, fluoro, chloro, bromo, C₁-C₄ alkyl, halogenated C₁-C₄ alkyl, halogenated C₁-C₄ alkoxy;

Particularly preferred R¹ is fluorine, chlorine, methyl, —CF₃, —CF₃O.

More preferred R² is H, halogen or C₁-C₆ alkyl;

Especially preferred R² is H, halogen or C₁-C₄ alkyl;

Particularly preferred R² is hydrogen.

More preferred R⁴ is more preferably H;

Especially preferred R⁴ is H;

Particularly preferred R⁴ is H.

More preferred R⁵ is H, halogen or C₁-C₆ alkyl;

Especially preferred R⁵ is H, fluoro, chloro, bromo or C₁-C₄ alkyl;

Particularly preferred R⁵ is H, fluorine, chlorine or methyl.

Preferred R³ is H, halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl sulphanyl, halogenated C₁-C₁₀ alkoxy, halogenated C₁-C₁₀ alkylsulphanyl or halogenated C₁-C₁₀ alkyl;

More preferred R³ is fluoro, chloro, bromo, iodo, C₁-C₆ alkoxy, C₁-C₆ alkyl sulphanyl, halogenated C₁-C₆ alkoxy, halogenated C₁-C₆ alkylsulphanyl or halogenated C₁-C₆ alkyl;

Especially preferred R³ is bromo, iodo, C₁-C₄ alkylsulphanyl, halogenated C₁-C₄ alkoxy, or halogenated C₁-C₄ alkyl;

Particularly preferred R³ is bromo, iodo, —SCH₃, —OCF₃, —CF₃.

Preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

each of R⁷, R⁸ and R⁹ is independently H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from hydroxyl, oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁷ and R⁸, together with the atom to which they are attached, form a substituted or unsubstituted 3- to 10-member ring; wherein each group is optionally substituted with one or more substituents independently selected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

or

R⁸ and R⁹, together with the atom to which they are attached, form a substituted or unsubstituted 3- to 10-member ring; wherein each group is optionally substituted with one or more substituents independently selected from halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R″″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R¹⁰ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl is optionally substituted with one or more groups independently selected from oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R″ and R′″ are independently hydrogen, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

or

any two of R′, R″, R′″ and R″″, together with the atom to which they are attached, form a 4- to 10-member heteroaryl or heterocyclic ring, wherein each of heteroaryl and heterocyclic rings is optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl.

More preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

More preferred R⁷ is C₁-C₆ alkyl substituted with 1 to 6 hydroxy groups, or (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl;

More preferred R⁸ is hydrogen or C₁-C₆ alkyl.

Especially preferred R⁶ is —C(O)NR⁸OR⁷ or —C(O)NR⁸R⁷;

Especially preferred R⁷ is C₁-C₄ alkyl substituted with 1 to 3 hydroxy groups, or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

Especially preferred R⁸ is hydrogen or C₁-C₄ alkyl.

Particularly preferred R⁶ is —C(O)NHOR⁷ or —C(O)NHR⁷.

Particularly preferred R⁷ is ethyl, propyl or isobutyl substituted with 1 to 3 hydroxy groups, or (C₃-C₆ cycloalkyl) C₁-C₄ alkyl.

In some preferred embodiments, the compound is of the formula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for the preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups described above.

In some more preferred embodiments, the compound is of the formula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for the more preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups described above.

In some especially preferred embodiments, the compound is of the formula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for the especially preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups described above.

In some particularly preferred embodiments, the compound is of the formula (A-I), where X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ are as defined for the particularly preferred variations for the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups described above.

It is intended and understood that each and every variations of the X¹, X², R¹, R², R³, R⁴, R⁵ and R⁶ groups of the compound of the formula (A-I) may be combined, that is, the non-preferred variations and variations with different degrees of preferences as specified above for the formula (A-I) may be combined. Such combinations are applicable to the synthetic precursors and intermediates as they are applied to the final product in the synthetic methods and schemes, for example, in Schemes A-1, A-2, A-3 and A-4.

Saturated or unsaturated hydrocarbon radicals (e.g., C₁-C₁₀ alkyl, alkylene or alkenyl), as well as when they are attached a heteroatom (e.g., alkoxy) may be a linear or branched chain.

Unless otherwise specified, any groups may be optionally substituted with a single substituent or with multiple substituents, and the substituents in a multiply substituted group may be the same or different.

In some embodiments, provided is a compound of the formula (A-I-1-a-1), (A-I-1-b-1), (A-I-1-c-1), (A-I-2-a-1), (A-I-2-b-1) or (A-I-2-c-1):

or a salt, prodrug or solvate thereof, wherein the —C(O)NHOR⁷ moiety is selected from the group consisting of:

and R¹, R³ and R⁵ are as described in Table 4.

TABLE 4 R¹ R³ R⁵ R¹ R³ R⁵ R¹ R³ R⁵ F Br F F Br Me F Br H F I F F I Me F I H F SMe F F SMe Me F SMe H F OCF₃ F F OCF₃ Me F OCF₃ H Cl Br F Cl Br Me Cl Br H Cl I F Cl I Me Cl I H Cl SMe F Cl SMe Me Cl SMe H Cl OCF₃ F Cl OCF₃ Me Cl OCF₃ H Me Br F Me Br Me Me Br H Me I F Me I Me Me I H Me SMe F Me SMe Me Me SMe H Me OCF₃ F Me OCF₃ Me Me OCF₃ H Synthesis

Compounds of the formula (A-I) or any variations thereof may be synthesized following synthetic routes illustrated in Schemes (A-1-1), (A-2-1), (A-3-1) and (A-4-1).

The synthetic route according to Scheme A-1-1 is further illustrated by a synthetic process for 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide as outline in Scheme A-1-1-1 and the following steps.

Step 1:

2,3,4-Trifluorophenol was protected with hydroxy protection reagent (examples include BnBr, BnCl) at ambient temperature in the presence of base (include Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuOK, t-BuONa) in appropriate inert solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). 1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventional workup.

Step 2:

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene in appropriate inert solvent (such as, but not limited to, aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) was added strong base (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The stirring was maintained at this temperature for several hours (such as 0.5-12 h, prefer 0.5-2 h). The mixture was transferred to a bottle with dry ice. The mixture is stirred for some time (such as 3-12 h, prefer 5-10 h). 5-Benzoxy-2,3,4-trifluorobenzoic acid is obtained after conventional workup.

Step 3:

5-Benzoxy-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) under strong basic condition (such as LDA, n-BuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) for some time (such as 3-12 h, prefer 5-10 h). 5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.

Step 4:

5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be protected by acid or hydroxyl protection reagent (such as BnBr, BnCl) at ambient temperature in the presence of base (includes Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuOK, t-BuONa) in appropriate inert solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Step 5:

Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate can be reacted with azide (such as NaN₃, KN₃) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Step 6:

Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethyl acetate, methyl acetate), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol, ethanol, propan-1-ol and water) for some time (1-12 h, prefer 3-10 h). 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid is obtained after conventional workup.

Step 7:

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid can be cyclized in the presence of acid (such as p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, formic acid, acetic acid, sulfuric acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane) for some time (0.2-12 h, prefer 0.5-10 h). 4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.

Step 8:

4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with halogenations reagent (such as NIS) in the presence of acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, acetic acid) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.

Step 9:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxyl can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent (such as HOBt, EDCI, HATU, TBTU) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.

Step 10:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide can be reacted in the presence of acid (such as hydrochloric acid, sulfuric acid, trifluoroacetic acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA DMPU, prefer dichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)beno[d]oxazole-6-carboxamide is obtained after conventional workup.

The synthetic route according to Scheme A-2-1 is further illustrated by a synthetic process for 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide as outline in Scheme A-2-1-1 and the following steps.

Step 1:

To a solution of 2,3,4-trifluorobromobenzene in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) was added strong base (such as LDA, nBuLi, LiHDMS) at low temperature (−50-−80° C., prefer −78° C.) under nitrogen atmosphere. The reaction is kept stirring for some time (0.5-12 h, prefer 0.5-2 h) and is added dry ice. After several hours (3-12 h, prefer 5-10 h), 5-bromo-2,3,4-trifluorobenzoic acid is obtained after conventional workup.

Step 2:

5-Bromo-2,3,4-trifluorobenzoic acid can be reacted with halogenated aniline (such as o-fluoroaniline, o-chloroaniline, o-bromoaniline, o-iodoaniline) in the presence of base (such as LDA, n-BuLi, LiHDMS) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), sulfolane, HMPA, DMPU, prefer anhydrous THF, ethyl ether and dioxane) at low temperature (−50-−80° C., prefer −78° C.) for some time (such as 3-12 h, prefer 5-10 h). 5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid is obtained after conventional workup.

Step 3:

5-Bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be reacted with MeOH in the presence of SOCl₂ in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol and ethanol). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). Methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.

Step 4:

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dioxane) was added base (such as aliphatic and aromatic amine (such as, but not limited to, N-ethyl-N-isopropylpropan-2-amine, triethylamine, diethylamine, DBU, t-butylamine, cyclopropanamine, dibutylamine, diisopropylamine, 1,2-dimethylpropanamine), inorganic base (such as Na₂CO₃, K₂CO₃, NaHCO₃, KHCO₃, t-BuONa, t-BuOK), prefer N-ethyl-N-isopropylpropan-2-amine) at ambient temperature under nitrogen atmosphere, followed by Pd catalyst (such as tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone) palladium, bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphinepalladium)acetate, prefer tris(dibenzylideneacetone)dipalladium) and phosphine ligand (such as dimethylbisdiphenylphosphinoxanthene, tri-tert-butylphosphine, tri-p-tolylphosphine, tris(4-chlorophenyl)phosphine, triisopropylphosphine, tris(2,6-dimethoxyphenyl)phosphine, 1,1′-bis(diphenylphosphino)ferrocene, prefer dimethylbisdiphenylphosphinoxanthene). The reaction is kept stirring at high temperature (80-130° C., prefer 90-110° C.) for some time (8-24 h, prefer 12-18 h). Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Step 5:

Methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be reacted with azide (such as NaN₃, KN₃) at high temperature (60-120° C., prefer 80-100° C.) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Step 6:

Methyl 4-azido-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxy benzyl)thio)benzoate can be hydrogenated catalyzed by appropriate catalyst (such as Pd/C, Pt, Ni) in the solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ester (such as ethyl acetate, methyl acetate), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methanol, ethanol, propan-1-ol and water) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate is obtained after conventional workup.

Step 7:

4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate can be deprotected in the presence of acid (such as CF₃COOH, HCOOH, CH₃COOH and n-C₅H₁₁COOH, prefer CF₃COOH) at certain temperature (20-75° C., prefer 25-75° C.) in appropriate aromatic aliphatic ether (such as anisole and phenetole, prefer anisole) for some time (1-12 h, prefer 3-10 h). Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate is obtained after conventional workup.

Step 8:

Methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercapto benzoate can be cyclized in the presence of acid (such as p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, formic acid, acetic acid, sulfuric acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane) for some time (0.2-12 h, prefer 0.5-10 h). Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.

Step 9:

Methyl 4-fluoro-5((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid (such as trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, formic acid, acetic acid) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer N,N-dimethylformamide and N,N-dimethylacetamide) for some time (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate is obtained after conventional workup.

Step 10:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent (such as HOBt, EDCI, HATU, TBTU) at ambient temperature in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane, 1,2-dichloroethane and N,N-dimethylformamide) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide is obtained after conventional workup.

Step 11:

4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide can be reacted in the presence of acid (such as HCl, H₂SO₄, trifluoroacetic acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.

The synthetic route according to Scheme A-3-1 is further illustrated by a synthetic route for 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]oxadiazole-6-carboxamide as outline in Scheme A-3-1-1.

The synthetic route according to Scheme A-1-1 is further illustrated by a synthetic process for 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide as outline in Scheme A-4-1-1.

In the synthetic processes described in Schemes (A-1-1), (A-2-1), (A-3-1) and (A-4-1), R¹, R², R³, R⁴, R⁵ and R¹¹ are as defined for the formula (A-I) or any variations thereof, such as the preferred variations, the more preferred variations, the especially preferred variations and the particularly preferred variations of R¹, R², R³, R⁴, R⁵ and R¹¹ as describe here above, or any combinations thereof;

Preferred R⁷ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl, C₆-C₁₄ aryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, heteroaryl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl or (heterocycloalkyl)C₁-C₁₀ alkyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl is optionally substituted with one or more groups independently selected from hydroxyl, oxo-, halogen, cyano, nitro, —CF₃, azido, —NR′SO₂R″, —SO₂NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SR′, —S(O)R″″, —SO₂R¹¹, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

R′, R″ and R′″ are independently H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl, or (C₆-C₁₄ aryl)C₁-C₁₀ alkyl;

R″″ is C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₆-C₁₄ aryl or (C₆-C₁₄ aryl) C₁-C₁₀ alkyl;

or any two of R′, R″, R′″ and R″″, together with the atom to which they are attached, form a 4- to 10-member heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C₆-C₁₄ aryl, heteroaryl, (C₆-C₁₄ aryl)C₁-C₁₀ alkyl, (heteroaryl)C₁-C₁₀ alkyl, heterocycloalkyl and (heterocycloalkyl)C₁-C₁₀ alkyl;

More preferred R⁷ is C₁-C₆ alkyl optionally substituted with 1 to 6 hydroxy groups, or (C₃-C₁₀ cycloalkyl)C₁-C₁₀ alkyl;

Especially preferred R⁷ is C₁-C₄ alkyl optionally substituted with 1 to 3 hydroxy groups, or (C₃-C₈ cycloalkyl)C₁-C₆ alkyl;

Particularly preferred R⁷ is ethyl, propyl or isobutyl which are optionally substituted with 1 to 3 hydroxy groups, or (C₃-C₆ cycloalkyl)C₁-C₄ alkyl.

Preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, benzyl substituted with 1 to 3 methoxy, C₁-C₄ alkyl, or —SiR¹⁶R¹⁷R¹⁸, wherein R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl;

More preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, benzyl substituted with 1 to 2 methoxy, C₁-C₄ alkyl, tert-butyldimethylsilyl, triphenylsilyl, trimethylsilyl, triethylsilyl, tripropylsilyl or triisopropylsilyl;

Especially preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl or C₁-C₂ alkyl; Particularly preferred R¹², R¹³, R¹⁴ and R¹⁵ are independently benzyl, p-methoxybenzyl or methyl.

Pharmaceutical Compositions

Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

The present invention embraces the free base of compounds detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, as well as the pharmaceutically acceptable salts and stereoisomers thereof. The compounds of the present invention can be protonated at the N atom(s) of an amine and/or N containing heterocycle moiety to form a salt. The term “free base” refers to the amine compounds in non-salt form. The encompassed pharmaceutically acceptable salts not only include the salts exemplified for the specific compounds described herein, but also all the typical pharmaceutically acceptable salts of the free form of compounds detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. The free form of the specific salt compounds described may be isolated using techniques known in the art. For example, the free form may be regenerated by treating a salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of the basic compounds are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.

The invention also provides pharmaceutical compositions comprising one or more compounds detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.

Medical Uses

Benzoheterocyclic compounds of the invention, such as such as benzothiadiazole, benzoxazole and benzothiazole derivatives detailed herein, are inhibitors of protein kinases such as MEK. The compounds may be useful in the treatment of conditions or disorders where the MEK cascade is implicated such as cancer and inflammatory diseases.

The invention provides compounds for use in the treatment or prevention of diseases or conditions which can be ameliorated by the inhibition of MEK. Thus, the present invention provides a compound, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, for use in the manufacture of a medicament for the treatment or prevention of diseases or conditions which can be ameliorated by the inhibition of MEK, such as cancer, acute and chronic inflammatory disease, a skin disease, diabetes, an eye disease, vasculogenesis, angiogenesis, or chronic pain.

In some embodiments, the disease or conditions treatable may include tumor (non-limiting examples include: hemangioma, glioma, melanoma, Kaposi's sarcoma, ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, colorectal cancer and gastrointestinal cancer), chronic inflammatory disease (non-limiting examples include: rheumatoid arthritis), disease related to vasculogenesis or angiogenesis of mammals, atherosclerosis, inflammatory bowel disease, dermatopathya (non-limiting examples include: psoriasis, excema and scleroderma), diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, diseases related to chronic pain (including neuralgia and pain arising from other diseases related to MEK; non-limiting examples include: phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic, postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain and limb amputation).

Also provided is a method for the treatment or prevention of a disease or condition mediated by MEK, said method comprises administering to an individual in need thereof a therapeutically effective amount of a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, or a composition comprising a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. In some embodiments, the disease or condition mediated by MEK is cancer, chronic inflammatory disease, a skin disease, diabetes, an eye disease, vasculogenesis, angiogenesis or chronic pain.

In some embodiments, the invention provides a method for the treatment or prevention of cancer, comprising administration to an individual in need thereof of an effective amount of a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, or a composition comprising a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. In some embodiments, the cancer is a cancer detailed below. In some embodiments, the cancer is colon cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, breast cancer, ovarian cancer, prostate cancer or skin cancer (e.g. melanoma).

In some embodiments, the invention provides a method for the treatment or prevention of inflammatory diseases, comprising administration to an individual in need thereof of an effective amount of a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof or a composition comprising a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. In some embodiment, the inflammatory disease is the rheumatoid arthritis or inflammatory bowel disease.

The compounds of the invention are useful for the treatment of inflammatory diseases, including conditions resulting from organ transplant rejection; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory diseases of the eye; chronic inflammatory diseases of the gum; inflammatory diseases of the kidney; inflammatory diseases of the skin; inflammatory diseases of the central nervous system; inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease, and atherosclerosis; as well as various other diseases that can have significant inflammatory components, including preeclampsia, chronic liver failure, brain and spinal cord trauma.

The present invention also provides a compound, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, for use in the manufacture of a medicament for treating or preventing inflammatory diseases.

In some embodiments, the invention provides a method for the treatment chronic pain, comprising administration to an individual in need thereof of an effective amount of a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof or a composition comprising a compound detailed herein, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof. In some embodiment, the chronic pain is phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic pain, postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain and limb amputation.

The compounds of this invention, such as a compound of the formula (I), (J), (K), (A-I) or any variations thereof, may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients, diluents, adjuvants, fillers, buffers, stabilizers, preservatives, lubricants, in a pharmaceutical composition, according to standard pharmaceutical practice.

Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. As a skilled artisan would understand, the dosage may be determined using known methods, and taking into consideration the age, body weight and health of the individual in need, the type of condition treated and presence of other drugs available. In some embodiments, the effective dose is about 0.1 to about 1000 mg/kg body weight. In some embodiment, the effective dose is about 1 to about 300 mg/kg body weight. For an average adult, a daily dose may be about 10 to 2500 mg, about 100 mg, about 200 mg, about 300 mg or about 400 mg.

The compounds of this invention may be administered to an individual by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, (e.g. by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal); and by implant of a depot (e.g. subcutaneously or intramuscularly). The individual may be an animal or a human.

The compounds may be administered in any suitable dosage forms such as solution, emulsion, water and oil suspension, powder, paste, soluble powder, granules, suspension emulsion thickener, capsule, tablet, potion, draught, pills, suppositories, and other suitable forms.

In some embodiments, the method of treating a disease on condition mediated by MEK, such as cancer, further comprises one or more additional active agent used in combination with a compound of the invention.

EXAMPLES

Compounds detailed herein may be prepared by those of skill in the art by referral to the General Method. Particular examples of the General Method are provided in the Examples below. The following Examples are provided to illustrate but not to limit the invention.

Example 1 Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide (Compound 1)

Step 1: 1-benzyloxy-2,3,4-trifluorobenzene

Sodium carbonate (19.50 g, 183.96 mmol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 92.10 mmol) in acetone (300 mL). To the stirred suspension was added benzyl bromide (17.31 g, 101.21 mmol) dropwisely. The mixture was heated under reflux at 50° C. for 24 h. The acetone was removed under reduced pressure and the residue was dissolved in water (300 mL). The solution was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 5% sodium hydroxide (100 mL) and brine (100 mL) sequentially and dried over Na₂SO₄. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90.7% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).

Step 2: 5-benzyloxy-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (m, 6H), 5.14 (s, 2H).

Step 3: 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (15.23 g, 137 mmol) and 5-benzyl-oxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF (120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.50 mmol) dropwisely. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 19.17 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.76 (s, 1H), 8.58 (s, 1H), 7.61 (dd, J=8.8, 1.7 Hz, 1H), 7.44 (m, 5H), 7.20 (m, 1H), 7.05 (m, 1H), 6.90 (m, 2H), 5.26 (s, 2H).

Step 4: benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (150 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and water was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as white solid (21.42 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.41 (m, 10H), 7.09 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).

Step 5: benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g, 46.22 mmol) in DMF (150 mL) was added NaN₃ (3.61 g, 55.46 mmol). The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 14.63 g, 65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.45 (s, 1H), 7.49 (s, 1H), 7.39 (m, 10H), 7.07 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.83 (m, 1H), 5.31 (s, 2H), 5.13 (s, 2H).

Step 6: 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid

To a solution of benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (14.63 g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was concentrated in vacuo to give the desired product, which was used directly in next step without further purification.

Step 7: 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid

To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.05 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (0.23 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (200 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 82.7% yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.05 (m, 2H), 6.86 (m, 1H).

Step 8: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid

To a solution of 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid (7.22 g, 24.88 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol) followed by trifluoroacetic acid (1.0 mL). After stirring for 5 h at ambient temperature, the reaction was quenched by saturated NH₄Cl (aq.). The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) successively, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (brown solid, 6.34 g, 61.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.58 (s, 1H), 8.18 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.55 (m, 1H).

Step 9: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (500 mg, 1.2 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 100:1, v/v) and gave the desired product (white solid, 450 mg, 74.8% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=10.8 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.50 (dd, J=13.9, 6.6 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.18 (d, J=14.5 Hz, 1H), 3.99 (m, 3H), 3.83 (s, 2H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]oxazole-6-carboxamide

To a solution of compound 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (450 mg, 0.9 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 6.7 mL, 6.72 mmol). After stirring for 1 h, the reaction mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (10 mL×2). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (white solid, 380 mg, 88.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.39 (m, 1H), 4.70 (s, 1H), 3.83 (s, 2H), 3.56 (s, 2H). MS APCI (+) m/z: 476.1, [M+H].

Example 1A Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide (Compound 1)

Step 1: 1-benzyloxy-2,3,4-trifluorobenzene

Sodium carbonate (19.50 g, 0.184 mol) was dispersed into a solution of 2,3,4-trifluorophenol (13.64 g, 0.092 mol) in acetone (300 mL). To the stirred suspension was added the solution of benzyl bromide (17.31 g, 101.21 mmol) in acetone (100 mL) dropwisely. The mixture was heated under reflux at 50° C. for 24 h, allowed to cool to room temperature, and filtered. The filter cake was washed with acetone (50 mL×3), and acetone was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL). The solution was washed with 5% sodium hydroxide (50 mL), water (150 mL) and brine (150 mL) sequentially and dried over Na₂SO₄. The solvent was removed in vacuo to yield a pale yellow solid (19.89 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.40 (m, 5H), 6.85 (m, 1H), 6.64 (m, 1H), 5.15 (s, 2H).

Step 2: 5-benzyloxy-2,3,4-trifluorobenzoic acid

To a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.6 mmol) in anhydrous THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 42.6 mL, 85.2 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice (20.0 g, 454.5 mmol). The mixture was stirred overnight at ambient temperature. The reaction was quenched with 10% aqueous HCl (300 mL). The mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 with concentrated HCl (aq.) and extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 14.01 (s, 1H), 7.42 (6H, m), 5.16 (2H, s).

Step 3: 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (13.21 g, 137.1 mmol) and 5-benzyl-oxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.55 mmol) in THF (120 mL) at −78° C. was added LiHMDS (206.1 mL, 1 M in THF, 206.1 mmol) dropwisely. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with HCl (aq., 1 N, 250 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 19.17 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.76 (s, 1H), 8.58 (s, 1H), 7.61 (dd, J=8.8, 1.7 Hz, 1H), 7.52-7.35 (m, 5H), 7.20 (m, 1H), 7.05 (m, 1H), 6.98-6.82 (m, 2H), 5.26 (s, 2H).

Step 4: benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (30 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and then water (150 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the corresponding product (21.42 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.46-7.36 (m, 10H), 7.12-7.06 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).

Step 5: benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g, 46.26 mmol) in DMF (35 mL) was added NaN₃ (3.61 g, 55.51 mmol). The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 14.63 g, 65% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 7.53 (dd, J=8.5, 2.1 Hz, 1H), 7.50-7.33 (m, 10H), 7.09 (m, 1H), 7.05 (m, 1H), 6.90 (m, 1H), 6.83 (m, 1H), 5.35 (s, 2H), 5.20 (s, 2H).

Step 6: 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid

To a solution of benzyl 4-azido-5-benzyloxy-3-fluoro-2-((2-fluorophenyl)amino)benzoate (14.63 g, 30.07 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (2.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 6 h at ambient temperature. After the insoluble matter was filtered off, the solvent was concentrated in vacuo to give the crude product (7.58 g, 90% yield), which was used directly in next step without further purification.

Step 7: 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid

To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.08 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (233 mg, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 92% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.85 (m, 1H).

Step 8: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo oxazole-6-carboxylic acid

To a solution of 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid (7.22 g, 24.90 mmol) in DMF (50 mL) was added NIS (6.08 g, 26.37 mmol) followed by trifluoroacetic acid (3 mL). After stirring for 4 h at ambient temperature, the reaction was quenched with saturated NH₄Cl (aq., 100 mL). The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (50 mL×3) and brine (100 mL) successively, dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 3:1, v/v) and gave the desired product (brown solid, 6.339 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.58 (dd, J=11.0, 1.7 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.55 (m, 1H).

Step 9: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo oxazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (500 mg, 1.2 mmol) in CH₂Cl₂ was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq., 20 mL). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product (white solid, 598 mg, 98% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=10.8 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 6.50 (dd, J=13.9, 6.6 Hz, 1H), 6.40 (d, J=6.0 Hz, 1H), 4.18 (d, J=14.5 Hz, 1H), 3.99 (m, 3H), 3.83 (s, 2H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo oxazole-6-carboxamide

To a solution of compound 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (598 mg, 1.17 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 6.7 mL, 6.72 mmol) dropwise. After stirring for 1 h, the reaction mixture was treated with saturated NaHCO₃ (aq.). The organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 15:1, v/v) and gave the desired product (white solid, 290 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.96 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.53 (d, J=9.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 6.39 (m, 1H), 4.70 (s, 1H), 3.83 (m, 2H), 3.56 (m, 2H). MS (ES+): m/z 476.34 [MH⁺].

Example 2 Preparation of N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide (Compound 2)

Step 1: N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (500 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (488 mg) was used directly in the next step without further purification.

Step 2: N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide

To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide (488 mg, 0.89 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford the desired product (white solid, 310 mg, 48% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.40 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 527.8, [M+Na].

Example 3 Preparation of 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide (Compound 3)

Step 1: 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid

To a solution of 2-chloroaniline (13.91 ml, 137.00 mmol) and 5-benzyloxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF (120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.5 mmol) dropwisely under nitrogen atmosphere. The mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 23.80 g, 89.1% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.80 (s, 1H), 8.66 (s, 1H), 7.64 (m, 1H), 7.34 (m, 7H), 6.92 (m, 1H), 6.78 (m, 1H), 5.26 (s, 2H).

Step 2: benzyl 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate

To a solution of 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid (23.80 g, 61.06 mmol) in DMF (200 mL) was added potassium bicarbonate (9.16 g, 91.6 mmol) followed by benzyl bromide (8.0 mL, 67.37 mmol). The mixture was stirred for 5 h at room temperature and water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as white solid (27.82 g, 95% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.56 (s, 1H), 7.52 (dd, J=8.5, 2.1 Hz, 1H), 7.40 (m, 11H), 7.15 (m, 1H), 6.88 (m, 1H), 6.74 (m, 1H), 5.34 (s, 2H), 5.16 (s, 2H).

Step 3: benzyl 4-azido-5-(benzyloxy)-2-((2-chlorophenyl)amino)-3-fluorobenzoate

To a solution of benzyl 5-(benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoate (27.82 g, 57.97 mmol) in DMF (250 mL) was added NaN₃ (4.52 g, 69.56 mmol). The mixture was stirred at 90° C. for 3 h. Then water (400 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (150 mL) and brine (150 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 22.97 g, 78.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.41 (s, 1H), 7.40 (m, 12H), 7.13 (m, 1H), 6.87 (m, 1H), 6.69 (m, 1H), 5.34 (s, 2H), 5.17 (s, 2H).

Step 4: 4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxy benzoic acid

To a solution of compound benzyl 4-azido-5-(benzyloxy)-2-((2-chlorophenyl)amino)-3-fluorobenzoate (22.97 g, 45.67 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.80 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated under reduced pressure to give the desired product, which was used directly in the next step without further purification.

Step 5: 5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid

To a solution of 4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxybenzoic acid in trimethyl orthoformate (100 mL) was added p-TsOH (0.42 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford a yellow solid (12.31 g, 87.9% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 13.9 (s, 1H), 9.05 (s, 1H), 8.8 (s, 1H), 8.23 (s, 1H), 7.43 (m, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 6.74 (m, 1H).

Step 6: 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid

To a solution of 5-((2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (12.31 g, 40.14 mmol) in DMF (100 mL) was added NBS (7.86 g, 44.15 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by water and the precipitate was filtered. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (pale brown solid, 10.82 g, 69.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 9.42 (s, 1H), 8.96 (s, 1H), 8.27 (s, 1H), 7.82 (d, J=12.0 Hz, 1H), 7.37 (m, 1H), 6.65 (m, 1H).

Step 7: 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-(vinyl-oxy)ethoxy)benzo[d]oxazole-6-carboxamide

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (463 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (445 mg) was used directly in the next step without further purification.

Step 8: 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide (445 mg, 0.95 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl solution (6.7 mL, 6.72 mmol). After stirring for 1 h, the reaction mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combined organic layer was washed with water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (white solid, 347 mg, 65% yield for two steps). ¹H NMR (400 MHz, MeOD): δ 8.65 (s, 1H), 7.8 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.24 (m, 1H), 6.50 (m, 1H), 3.95 (s, 2H), 3.70 (s, 2H). MS APCI (+) m/z: 445.9[M+H], 467.8, [M+Na].

Example 4 Preparation of 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide (Compound 4)

Step 1: 5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (463 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-di-oxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (473 mg) was used directly in the next step without further purification.

Step 2: 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluorobenzo[d]oxazole-6-carboxamide (473 mg, 0.92 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and washed with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford the desired product (white solid, 255 mg, 44.7% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.42 (m, 1H), 4.83 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.70 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 475.7, [M+H].

Example 5 Preparation of N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide (Compound 5)

Step 1: 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid (70 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29 mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 62 mg, 89.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.67 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (m, 1H), 7.39 (s, 1H).

Step 2: 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.07 mmol) in CH₂Cl₂ (3 mL) was added triethylamine (22 mg, 0.22 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (16 mg, 0.11 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (40 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 3.40 (m, 1H), 1.71 (m, 2H), 0.91-0.85 (m, 2H).

Step 3: N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide

To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodo phenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.06 mmol) in THF (3 mL) was added potassium trimethylsilanolate (12 mg, 0.09 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product as a white solid (10 mg, 35.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, 1H), 7.88 (s, 1H), 7.46 (dd, 1H), 7.33 (s, 1H), 7.23 (dd, 1H), 6.15 (m, 1H), 5.49 (s, 1H), 2.55 (m, 1H), 1.01 (m, 2H), 0.92 (m, 2H). MS APCI (+) m/z: 492.5, [M+H].

Example 6 Preparation of 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide (Compound 6)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.24 mmol) in DCM (5 mL) was added triethylamine (74 mg, 0.73 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (66 mg, 0.36 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 89.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.70-7.68 (d, 2H), 7.27 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (120 mg, 0.23 mmol) in THF (10 mL) was added potassium trimethylsilanolate (48 mg, 0.35 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (100 mg, 87.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.42 (m, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophen-yl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide (100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide (44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (30 mg, 28.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.46-7.36 (m, 2H), 7.30-7.20 (m, 1H), 6.82 (s, 1H), 6.45-6.32 (m, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 2.86-2.79 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.20 (m, 4H). MS APCI (+) m/z: 566.3, [M+H].

Example 7 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)cyclopropanesulfonamide (Compound 7)

Step 1: 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (110 mg, 0.28 mmol) in t-BuOH (3 mL) was added DPPA (94 mg, 0.34 mmol) followed by triethylamine (58 mg, 0.57 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 105 mg, 96.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.69 (s, 1H), 7.99 (d, 1H), 7.77 (d, 1H), 7.51 (m, 1H), 7.41 (s, 1H).

Step 2: 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in CH₂Cl₂ (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (55 mg, 0.39 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (110 mg, 86.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.32 (m, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.88 (m, 2H).

Step 3: N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide

To a solution of 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.21 mmol) in THF (10 mL) was added potassium trimethylsilanolate (40 mg, 0.31 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) and the product was obtained as a white solid (60 mg, 63.4% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.97 (s, 1H), 7.40 (m, 2H), 7.31-7.26 (m, 1H), 6.81 (s, 1H), 6.40-6.36 (m, 1H), 6.23 (s, 1H), 5.86-5.72 (m, 1H), 5.25-5.13 (m, 2H), 2.85 (d, 2H), 1.30-1.22 (m, 2H), 1.15-1.20 (m, 2H). 8.17 (s, 1H), 7.97 (s, 1H), 7.49 (dd, 1H), 7.35 (s, 1H), 7.26 (dd, 1H), 6.17 (m, 1H), 5.44 (s, 1H), 2.57 (m, 1H), 1.06-1.08 (m, 2H), 1.00-1.01 (m, 2H). MS APCI (+) m/z: 461.7, [M+H].

Example 8 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (Compound 8)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one

To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.26 mmol) in DCM (10 mL) was added triethylamine (80 mg, 0.78 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (71 mg, 0.39 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the reaction was treated with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (20 mL×2). The combined organic phase was washed with water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 87.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.39-7.11 (d, 2H), 7.05, (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (120 mg, 0.23 mmol) in THF (5 mL) was added potassium trimethylsilanolate (32 mg, 0.23 mmol). The mixture was stirred at room temperature for 1 h and treated with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the product as a white solid (100 mg, 87.6% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.42 (d, 1H), 7.31-7.25 (m, 1H), 6.80 (s, 1H), 6.43-6.35 (m, 1H), 6.21 (s, 1H), 5.85-5.70 (m, 1H), 5.22-5.14 (m, 2H), 2.83 (d, 2H), 1.28-1.20 (m, 2H), 0.87-0.80 (m, 2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((4-bromo-2-chloro phenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]oxazol-6-yl)cyclopropane-1-sulfonamide (100 mg, 0.38 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide (44 mg, 0.38 mmol) followed by osmium tetraoxide (10 mg, 0.04 mmol) and water (0.5 mL). After stirring at room temperature overnight, the mixture was concentrated and then diluted with EA. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography to give the product as white solid (30 mg, 28.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.98 (s, 1H), 7.45-7.34 (m, 2H), 7.32-7.21 (m, 1H), 6.83 (s, 1H), 6.44-6.30 (m, 1H), 4.41-4.25 (m, 2H), 4.21-4.12 (m, 1H), 3.72-3.62 (m, 1H), 2.85-2.78 (m, 1H), 1.32-1.26 (m, 2H), 1.16-1.21 (m, 4H). MS APCI (+) m/z: 535.8, [M+H].

Example 9 Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide (Compound 9)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (17.54 g, 157.80 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120 mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 24.24 g, 88.8% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.01 (dd, J=7.4, 2.1 Hz, 1H), 7.25 (m, 1H), 7.10 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (24.24 g, 70.04 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as a white solid (22.33 g, 88.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H), 8.01 (dd, J=7.1, 2.3 Hz, 1H), 7.04 (m, 4H), 3.92 (s, 3H).

Step 4: methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd₂(dba)₃ (2.84 g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and 4-methoxy-α-toluenethiol (10.27 g, 65.11 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 24.35 g, 90.6% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.25 (m, 6H), 6.85 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).

Step 5: methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (24.35 g, 56.18 mmol) in DMF (200 mL) was added NaN₃ (4.38 g, 67.41 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 21.04 g, 82.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.10 (m, 6H), 6.84 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).

Step 6: methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (21.04 g, 46.09 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.46 g, 98.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.07 (s, 1H), 7.77 (s, 1H), 7.06 (m, 4H), 6.95 (m, 2H), 6.81 (d, J=8.3 Hz, 2H), 4.68 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).

Step 7: dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate)

To a solution of methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (19.46 g, 45.21 mmol) in CH₂Cl₂ (180 mL) was added DDQ (11.29 g, 49.73 mmol) followed by water (20 mL). After stirring at ambient temperature for 10 h, the reaction was quenched by saturated sodium bicarbonate (aq., 100 mL). The aqueous layer was extracted by CH₂Cl₂ (100 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the desired product (pale yellow solid, 9.81 g, 35.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.34 (s, 2H), 7.46 (s, 2H), 7.06 (m, 8H), 4.89 (br, 4H), 3.75 (s, 6H).

Step 8: methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate

To a solution of dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-fluorophenyl)amino)benzoate) (9.81 g, 15.86 mmol) in THF/MeOH (100 mL, 10:1, v/v) was added NaBH₄ (3.00 g, 79.29 mmol) portion-wise in 1 h. After stirring at ambient temperature for 1 h, the reaction was quenched with 10% HCl (aq.) and pH was adjusted to 1-2. The aqueous layer was extracted with CH₂Cl₂ (50 mL×3). The combined organic phase was washed with water (50 mL) and brine (50 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.

Step 9: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOH (0.61 g, 3.17 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.64 g, 85.1% yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s, 3H).

Step 10: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.64 g, 26.97 mmol) in DMF (100 mL) was added NIS (6.68 g, 29.67 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was treated by water (150 mL). The precipitate was filtered off and the filter cake was washed with water. The desired product was obtained as a yellow solid (10.34 g, 86.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 7.42 (d, J=10.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.63 (dd, J=15.0, 8.7 Hz, 1H), 3.97 (s, 3H).

Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid

To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (10.34 g, 23.17 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (9.51 g, 95.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.10 (s, 1H), 9.18 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 7.41 (m, 1H), 7.30 (m, 1H), 6.65 (m, 1H).

Step 12: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (519 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄ filtered, and concentrated in vacuo. The crude product (492 mg) was used directly in the next step without further purification.

Step 13: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (492 mg, 1.00 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (30 mL). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product as a white solid (446 mg, 75.9% yield for the two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 9.55 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.55 (d, J=11.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.48 (d, J=9.2 Hz, 1H), 4.72 (s, 1H), 3.84 (m, 2H), 3.57 (m, 2H). MS APCI (+) m/z: 491.8, [M+H].

Example 9A Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide (Compound 9)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of 1-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) in THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL, 67.8 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl (300 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 and extracted with ethyl acetate (200 mL×3). The combined organic extract was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (white solid, 13.51 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 13.94 (s, 1H), 7.95 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl₂ (60 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (300 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the corresponding product (gray solid, 12.58 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).

Step 4: methyl 3,4-difluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.6 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.2 mmol). Then Pd₂(dba)₃ (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and 4-methoxy-α-toluenethiol (5.48 g, 35.6 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere and then allowed to cool to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 12.64 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.06-7.44 (m, 6H), 6.82-6.88 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).

Step 5: methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g, 29.2 mmol) in DMF (30 mL) was added NaN₃ (2.28 g, 35.0 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.02-7.28 (m, 6H), 6.83-6.85 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).

Step 6: methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (10.38 g, 22.7 mmol) in MeOH (100 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred at ambient temperature for 6 h. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.79 g, 100% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s, 1H), 7.78 (s, 1H), 6.93-7.28 (m, 8H), 4.65 (s, 2H), 4.00 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H).

Step 7: methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate

To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate (9.79 g, 22.7 mmol) in anisole (12 mL) was added CF₃COOH (20 mL). After stirring at ambient temperature for 23 h, the solvent was removed in vacuo. To the residue was added water (30 mL). The mixture was neutralized with 25% aqueous ammonia and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (white solid, 5.28 g, 75% yield). The product was used directly in the next step without further purification.

Step 8: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate (2.07 g, 6.67 mmol) in trimethyl orthoformate (20 mL) was added p-TsOH (166 mg, 0.65 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (white solid, 1.963 g, 92% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.15-6.78 (m, 4H), 3.91 (s, 3H).

Step 9: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (1.963 g, 6.14 mmol) in DMF (10 mL) was added NIS (1.5 g, 6.5 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was treated by saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. After purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained as white solid (1.889 g, 69% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.03 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.18-6.72 (m, 3H), 3.91 (s, 3H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) in THF (6 mL) was added LiHMDS (2.5 mL, 1 M in THF, 2.5 mmol) at −78° C. After stirring at this temperature for 10 min, a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylate (360 mg, 0.81 mmol) in THF was syringed dropwisely. Then the mixture was allowed to warm to ambient temperature, quenched with saturated NH₄Cl (aq., 20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic extract was washed with water (10 mL×3) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. After purification by flash chromatography (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained (410 mg, 98% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.85 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=10.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.53 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).

Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (410 mg, 0.8 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol) dropwise. After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The organic layer was separated, washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 15:1, v/v) and the desired product was obtained as a white solid (290 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.83 (s, 1H), 8.92 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=9.4 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.41 (m, 1H), 4.72 (m, 1H), 3.85 (m, 2H), 3.59 (m, 2H). MS (ES+): m/z 492.35 [MH⁺].

Example 10 Preparation of N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide (Compound 10)

Step 1: N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (519 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (475 mg) was used directly in the next step without further purification.

Step 2: N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide (475 mg, 0.85 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford the desired product (white solid, 310 mg, 45.4% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 9.56 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.57 (d, 1H), 7.32 (d, 1H), 6.47 (m, 1H), 4.85 (d, 1H), 4.62 (m, 1H), 3.86 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: 522.5 [M+H].

Example 11 Preparation of 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide (Compound 11)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid

To a solution of 2-chloroaniline (20.13 g, 157.80 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120 mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 25.63 g, 89.6% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 14.10 (s, 1H), 9.30 (s, 1H), 8.03 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 7.04 (m, 2H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid (25.63 g, 70.69 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). The resulting solution was stirred at 85° C. overnight. Most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as a white solid (22.84 g, 85.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.15 (s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 3.95 (s, 3H).

Step 4: methyl 3,4-difluoro-2-((2-chlorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (22.84 g, 60.65 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (15.68 g, 121.30 mmol). Then Pd₂(dba)₃ (2.78 g, 3.03 mmol) followed by Xantphos (3.51 g, 6.06 mmol) and 4-methoxy-α-toluenethiol (10.27 g, 66.72 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 24.18 g, 88.6% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.14 (s, 1H), 7.77 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 3H), 7.19 (m, 1H), 7.01 (m, 1H), 6.88 (m, 2H), 4.02 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).

Step 5: methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (24.18 g, 53.75 mmol) in DMF (200 mL) was added NaN₃ (4.19 g, 64.49 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (200 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (pale yellow solid, 21.63 g, 85.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.01 (s, 1H), 7.80 (s, 1H), 7.33 (m, 4H), 7.15 (m, 1H), 6.90 (m, 1H), 6.85 (m, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).

Step 6: methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)-benzoate (21.63 g, 45.74 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (19.93 g, 97.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.99 (s, 1H), 7.82 (s, 1H), 7.21 (m, 1H), 7.17 (m, 3H), 6.87 (m, 3H), 6.69 (m, 1H), 4.63 (s, 2H), 3.85 (s, 5H), 3.81 (s, 3H).

Step 7: dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-chlorophenyl)amino)benzoate)

To a solution of methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (19.93 g, 44.6 mmol) in CH₂Cl₂ (180 mL) was added DDQ (11.25 g, 53.73 mmol) followed by water (20 mL). After stirring at ambient temperature for 10 h, the reaction was quenched by saturated sodium bicarbonate (aq., 100 mL). The aqueous layer was extracted by CH₂Cl₂ (100 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the desired product (pale yellow solid, 9.39 g, 32.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.33 (s, 2H), 7.46 (s, 2H), 7.40 (m, 2H), 7.15 (m, 2H), 6.92 (m, 2H), 6.76 (m, 2H), 4.86 (br, 4H), 3.80 (s, 6H).

Step 8: methyl 4-amino-3-fluoro-2-((2-chlorophenyl)amino)-5-mercaptobenzoate

To a solution of dimethyl 5,5′-disulfanediylbis(4-amino-3-fluoro-2-((2-chlorophenyl)amino)benzoate) (9.39 g, 14.41 mmol) in THF/MeOH (100 mL, 10:1, v/v) was added NaBH₄ (2.73 g, 72.05 mmol) portion-wise in 1 h. After stirring at ambient temperature for 1 h, the reaction was quenched with 10% HCl (aq.) and pH was adjusted to 1-2. The aqueous layer was extracted with CH₂Cl₂ (50 mL×3). The combined organic phase was washed with water (50 mL) and brine (50 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.

Step 9: methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl 4-amino-3-fluoro-2-((2-chlorophenyl)amino)-5-mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOH (0.58 g, 3.05 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.50 g, 87.6% yield for two steps). ¹H NMR (400 MHz, CDCl₃): δ 9.13 (s, 1H), 8.70 (s, 1H), 8.50 (s, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 3.93 (s, 3H).

Step 10: methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[c]thiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.50 g, 25.24 mmol) in DMF (100 mL) was added NBS (4.92 g, 27.76 mmol). After stirring for 5 h at ambient temperature, the reaction was treated by water (150 mL). The precipitate was filtered off and the filter cake was washed with water. The desired product was obtained as a pale brown solid (8.74 g, 83.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.17 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.65 (m, 1H), 7.30 (m, 1H), 6.63 (m, 1H), 3.98 (s, 3H).

Step 11: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylic acid

To a solution of methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.74 g, 21.02 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 9.5 mL). After stirring at ambient temperature for 2 h, the reaction was treated with 10% HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (8.08 g, 95.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.09 (s, 1H), 9.18 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 6.65 (m, 1H).

Step 12: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylic acid (482 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxyl-amine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄ filtered, and concentrated in vacuo. The crude product (503 mg) was used directly in the next step without further purification.

Step 13: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (503 mg, 1.03 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (30 mL). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product as a white solid (420 mg, 75.9% yield for the two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 9.53 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.56 (d, m, 1H), 7.33 (m, 1H), 6.50 (m, 1H), 4.75 (m, 1H), 3.83 (m, 2H), 3.58 (m, 2H). MS: m/z 461.9, [M+H].

Example 12 Preparation of N-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide (Compound 12)

Step 1: N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-chloro-4-bromophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylic acid (482 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added HOBt (254 mg, 1.63 mmol) followed by EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (238 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (30 mL×3). The combined organic extracts was washed by water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (490 mg) was used directly in the next step without further purification.

Step 2: N-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide

To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxamide (490 mg, 0.92 mmol) in CH₂Cl₂ (10 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) to afford the desired product (white solid, 345 mg, 58.6% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 9.54 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 6.46 (m, 1H), 4.84 (d, 1H), 4.60 (m, 1H), 3.88 (m, 1H), 3.74 (m, 2H), 3.36 (m, 2H). MS APCI (+) m/z: 491.9 [M+H].

Example 13 Preparation of N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide (Compound 13)

Step 1: 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxylic acid (75 mg, 0.17 mmol) in t-BuOH (3 mL) was added DPPA (82 mg, 0.29 mmol) followed by triethylamine (36 mg, 0.36 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (70 mg, 94.0% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.66 (s, 1H), 7.95 (d, 1H), 7.74 (d, 1H), 7.47 (t, 1H), 7.33 (s, 1H).

Step 2: 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (70 mg, 0.16 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (48 mg, 0.49 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (35 mg, 0.25 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over

Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (80 mg, 92% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.68 (s, 1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.45 (t, 1H), 3.35 (m, 1H), 1.69 (m, 2H), 0.91 (m, 2H).

Step 3: N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide

To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate (19 mg, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq., 5 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product as a white solid (30 mg, 63.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 8.02 (s, 1H), 7.91 (d, 1H), 7.86 (s, 1H), 7.76 (d, 1H), 7.45 (m, 1H), 5.52 (s, 1H), 2.85 (m, 1H), 1.29 (m, 2H), 1.20 (m, 2H). MS APCI (+) m/z: 508.5 [M+H].

Example 14 Preparation of 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide (Compound 14)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (35 mg, 0.74 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.18 mmol) and

DMAP (15 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 89.8% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 7.97 (s, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.46 (t, 1H), 5.76-5.60 (m, 1H), 5.06 (m, 2H), 2.91-2.81 (m, 1H), 2.11-2.01 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate (14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg, 91.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 7.97 (s, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.46 (m, 1H), 6.82 (s, 1H), 6.64 (s, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.00 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide (11 mg, 0.09 mmol) followed by osmium tetraoxide (3 mg, 0.01 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (20 mg, 37.7% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.68 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.75 (d, 1H), 7.45 (m, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 4.42-4.28 (m, 2H), 4.21-4.12 (m, 1H), 3.76-3.62 (m, 1H), 3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.80 (m, 4H). MS APCI (+) m/z: 582.5 [M+H].

Example 15 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide (Compound 15)

Step 1: 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazole-6-carboxylic acid (120 mg, 0.299 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.449 mmol) followed by triethylamine (60 mg, 0.598 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 100 mg, 83.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.76 (s, 1H), 8.65 (s, 1H), 7.95 (d, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.39 (s, 1H).

Step 2: 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one

To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (100 mg, 0.25 mmol) in CH₂Cl₂ (10 mL) was added triethylamine (76 mg, 0.75 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (53 mg, 0.38 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (15 mL×2). The combined organic phase was washed with water (15 mL) and brine (20 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 95.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.67 (s, 1H), 7.99 (s, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.50 (m, 1H), 3.37 (m, 1H), 1.70 (m, 2H), 0.93 (m, 2H).

Step 3: N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide

To a solution of 5-(4-bromo-2-chlorophenyl)-7-(cyclopropylsulfonyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.10 mmol) in THF (5 mL) was added potassium trimethylsilanolate (13 mg, 0.10 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) and the product was obtained (30 mg, 63.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 8.00 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.75 (d, 1H), 7.43 (m, 1H), 5.48 (s, 1H), 2.84 (m, 1H), 1.29 (m, 2H), 1.23 (m, 2H). MS APCI (+) m/z: 477.9, [M+H].

Example 16 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (Compound 16)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-c]thiazol-6(7H)-one

To a solution of 5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (50 mg, 0.13 mmol) in DCM (10 mL) was added triethylamine (38 mg, 0.38 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (34 mg, 0.19 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the reaction was treated with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (20 mL×2). The combined organic phase was washed with water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (62 mg, 91.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 7.98 (s, 1H), 7.91 (d, 1H), 7.76 (d, 1H), 7.48 (t, 1H), 5.76-5.63 (m, 1H), 5.08 (m, 2H), 2.90-2.83 (m, 1H), 2.10-2.00 (m, 1H), 1.96-1.88 (m, 2H), 1.26-1.15 (m, 2H).

Step 2: 1-allyl-N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-5-(4-bromo-2-chlorophenyl)-4-fluoro-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (60 mg, 0.111 mmol) in THF (5 mL) was added potassium trimethylsilanolate (15 mg, 0.111 mmol). The mixture was stirred at room temperature for 1 h and treated with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the product as a white solid (50 mg, 87.5% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.98 (s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.45 (m, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 5.75-5.60 (m, 1H), 5.03 (m, 2H), 2.92-2.81 (m, 1H), 2.12-2.01 (m, 1H), 1.93-1.85 (m, 2H), 1.20-1.11 (m, 2H).

Step 3: N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thia-zol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide (50 mg, 0.10 mmol) in THF (10 mL) was added N-methylmorpholine-N-oxide (12 mg, 0.1 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) and water (0.5 mL). After stirring at room temperature overnight, the mixture was concentrated and then diluted with EA. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography to give the product as white solid (25 mg, 46.9% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.96 (s, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.44 (m, 1H), 6.82 (s, 1H), 6.68 (s, 1H), 4.42-4.25 (m, 2H), 4.21-4.13 (m, 1H), 3.73-3.62 (m, 1H), 3.61-3.51 (m, 1H), 2.63-2.52 (m, 2H), 0.91-0.83 (m, 4H). MS APCI (+) m/z: 551.9, [M+H].

Example 17 Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (Compound 17)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 13.95 (s, 1H), 7.97 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (17.54 g, 157.80 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (20.12 g, 78.90 mmol) in THF (120 mL) was added LiHMDS (236.7 mL, 1 M in THF, 236.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 24.24 g, 88.8% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H), 8.01 (dd, J=7.4, 2.1 Hz, 1H), 7.25 (m, 1H), 7.10 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (24.24 g, 70.04 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as a white solid (22.33 g, 88.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H), 8.01 (dd, J=7.1, 2.3 Hz, 1H), 7.04 (m, 4H), 3.92 (s, 3H).

Step 4: methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd₂(dba)₃ (2.84 g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and BnSH (8.09 g, 65.11 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 22.09 g, 88.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.04 (s, 1H), 7.68 (dd, 1H), 7.18 (m, 5H), 6.97 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).

Step 5: methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.09 g, 54.76 mmol) in DMF (300 mL) was added NaN₃ (4.27 g, 65.71 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 19.43 g, 83.2% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s, 1H), 7.75 (d, 1H), 7.27 (m, 5H), 7.02 (m, 4H), 4.07 (s, 2H), 3.89 (s, 3H).

Step 6: methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluoro phenyl)amino)benzoate (19.43 g, 45.56 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (18.06 g, 99.0%). ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s, 1H), 7.78 (s, 1H), 7.11 (m, 9H), 4.65 (s, 2H), 3.88 (s, 2H), 3.84 (s, 3H).

Step 7: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (2.07 g, 5.17 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO₂ (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO₃ (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 8.57 (s, 1H), 7.08 (m, 4H), 4.03 (s, 3H).

Step 8: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (20 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 5 h at ambient temperature, the reaction was quenched by saturated NH₄Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na₂SO₄ and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.73 (s, 1H), 8.58 (d, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 6.74 (m, 1H), 4.03 (s, 3H).

Step 9: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid

To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (brown solid, 1.73 g, 94.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.87 (s, 1H), 8.84 (s, 1H), 7.62 (d, 1H), 7.40 (d, 1H), 6.78 (m, 1H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (200 mg, 0.49 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.69 mmol) and EDCI (140 mg, 0.69 mmol). The mixture was stirred for 1 h and O-(2-(vinyl-oxy)ethyl)hydroxylamine (72 mg, 0.69 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄ filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 50:1, v/v) and gave the desired product (yellow solid, 190 mg, 79.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 6.64 (dd, 1H), 6.42 (d, 1H), 4.21 (d, 1H), 4.01 (m, 3H), 3.83 (m, 2H).

Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (190 mg, 0.37 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (10 mL×2). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product as a yellow solid (154 mg, 84.6% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.88 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 6.42 (d, 1H), 4.69 (m, 1H), 4.05 (m, 2H), 3.80 (m, 2H). MS APCI (+) m/z: m/z 493.2, [M+H].

Example 17A Preparation of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (Compound 17)

Step 1: 5-bromo-2,3,4-trifluorobenzoic acid

To a solution of 1-bromo-2,3,4-trifluorobenzene (13.64 g, 64.6 mmol) in THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 33.9 mL, 67.8 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl (300 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 and extracted with ethyl acetate (200 mL×3). The combined organic extract was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the desired product (white solid, 13.51 g, 82% yield). ¹H NMR (400 MHz, CDCl₃): δ 13.94 (s, 1H), 7.95 (m, 1H).

Step 2: 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid

To a solution of 2-fluoroaniline (10.2 mL, 105.8 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (13.51 g, 52.9 mmol) in THF (120 mL) was added LiHMDS (158.7 mL, 1 M in THF, 158.7 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 13.73 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.01 (d, 1H), 7.26 (m, 1H), 7.01-7.16 (m, 3H).

Step 3: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (13.73 g, 39.6 mmol) in MeOH (300 mL) was added SOCl₂ (60 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (300 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the corresponding product (gray solid, 12.58 g, 90% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.09 (s, 1H), 8.05 (d, 1H), 7.00-7.14 (m, 4H), 3.94 (s, 3H).

Step 4: methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.80 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.60 mmol). Then Pd₂(dba)₃ (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.44 g, 35.80 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere. Then the reaction was allowed to warm to ambient temperature and quenched with water (150 mL). The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.64 g, 88% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.68 (dd, J=7.5, 2.1 Hz, 1H), 7.21-7.14 (m, 5H), 7.05-6.89 (m, 4H), 3.97 (s, 2H), 3.80 (s, 3H).

Step 5: methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g, 31.36 mmol) in DMF (30 mL) was added NaN₃ (2.45 g, 37.63 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 7.66 (s, 1H), 7.27-7.12 (m, 3H), 7.10-6.80 (m, 6H), 3.98 (s, 2H), 3.80 (s, 3H).

Step 6: methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluorophenyl)amino)benzoate (10.38 g, 24.36 mmol) in MeOH (100 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 6 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.79 g, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.69 (s, 1H), 7.19-7.17 (m, 3H), 7.15-6.83 (m, 6H), 4.54 (s, 2H), 3.79 (s, 2H), 3.75 (s, 3H).

Step 7: methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (2.07 g, 5.17 mmol) in acetic acid (60 mL) was added HCl (con., 8 mL) and water (6 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO₂ (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C. within 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO₃ (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic extract was washed with water (30 mL×3) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 8.48 (s, 1H), 7.00-6.90 (m, 4H), 3.94 (s, 3H).

Step 8: methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.53 g, 4.77 mmol) in DMF (10 mL) was added NIS (1.18 g, 5.24 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was quenched with saturated NH₄Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL×3) and brine (30 mL) successively, dried over Na₂SO₄ and concentrated in vacuo to give the desired product (yellow solid, 1.90 g, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H), 3.94 (s, 3H).

Step 9: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid

To a solution of methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.90 g, 4.25 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 1.0 M LiOH (aq., 10 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL×3) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (brown solid, 1.70 g, 94.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=10.3 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (dd, J=14.3, 8.3 Hz, 1H).

Step 10: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (1.7 g, 5.54 mmol) in CH₂Cl₂ (20 mL) was added HOBt (1.21 g, 8.31 mmol) and EDCI (1.59 mg, 8.31 mmol). The mixture was stirred for 1 h and O-(2-(vinyl-oxy)ethyl)hydroxylamine (0.69 g, 6.65 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq., 20 mL). The resultant mixture was extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts were washed with water (10 mL×3) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product (2.44 g, 85% yield). ¹H NMR (400 MHz, d6-DMSO) δ 11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).

Step 11: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (410 mg, 0.79 mmol) in CH₂Cl₂ (5 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The organic layer was separated, washed with water (30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product (343 mg, 88% yield). ¹H NMR (400 MHz, d6-DMSO) δ 11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 2H), 3.83 (m, 2H). MS (ES+): m/z 493.0 [M+H].

Example 18 Preparation of N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide (Compound 18)

Step 1: N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (210 mg, 0.48 mmol) in CH₂Cl₂ (10 mL) was added HOBt (105 mg, 0.72 mmol) followed by EDCI (138 mg, 0.72 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts was washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (229 mg) was used directly in the next step without further purification.

Step 2: N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide (229 mg, 0.41 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (30 mL×2) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford the desired product (yellow solid, 170 mg, 67.9% yield for two steps). ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 6.64 (m, 1H), 4.86 (m, 1H), 4.62 (m, 1H), 3.87 (m, 1H), 3.72 (m, 2H), 3.33 (m, 2H, covered by the peak of water). MS APCI (+) m/z: 522.9 [M+H].

Example 19 Preparation of 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (Compound 19)

Step 1: 5-bromo-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid

To a solution of 2-chloroaniline (12.56 g, 98.42 mmol) and 5-bromo-2,3,4-trifluorobenzoic acid (12.55 g, 49.21 mmol) in THF (120 mL) was added LiHMDS (147.6 mL, 1 M in THF, 147.6 mmol) dropwisely at −78° C. under nitrogen atmosphere. The mixture was allowed to slowly warm to room temperature and stirred at this temperature overnight. The reaction was quenched with 10% HCl (aq., 100 mL). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the desired product 4 (yellow solid, 13.74 g, 77% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 14.10 (s, 1H), 9.30 (s, 1H), 8.03 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 7.04 (m, 2H).

Step 2: methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate

To a solution of 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoic acid (13.74 g, 37.89 mmol) in MeOH (300 mL) was added thionyl chloride (20 mL). After stirring at 85° C. overnight, most MeOH was removed in vacuo. The residue was neutralized with saturated sodium bicarbonate (aq.) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the corresponding product as a gray white solid (12.98 g, 91.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.15 (s, 1H), 8.06 (m, 1H), 7.41 (m, 1H), 7.24 (m, 1H), 7.01 (m, 1H), 6.90 (m, 1H), 3.95 (s, 3H).

Step 3: methyl 5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.98 g, 34.47 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (8.86 g, 68.94 mmol). Then Pd₂(dba)₃ (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.48 g, 36.19 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N₂ atmosphere and then allowed to warm to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.44 g, 86.0% yield). ¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 7.79 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 5H), 7.18 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H).

Step 4: methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.44 g, 29.64 mmol) in DMF (100 mL) was added NaN₃ (2.89 g, 44.46 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 9.84 g, 75.1% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 1H), 7.65 (s, 1H), 7.45 (m, 1H), 7.33 (m, 4H), 7.24 (m, 2H), 6.95 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H).

Step 5: methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate

To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (9.84 g, 22.23 mmol) in MeOH (200 mL) was added and 10% palladium on carbon (1.55 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 2 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (9.26 g, 100%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 7.54 (s, 1H), 7.45 (m, 1H), 7.24 (m, 6H), 6.95 (m, 1H), 6.77 (m, 1H), 6.27 (s, 2H), 3.95 (s, 2H), 3.73 (s, 3H).

Step 6: methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (2.50 g, 5.99 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO₂ (0.45 g, 6.58 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO₃ (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.82 g, 90.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H), 8.59 (d, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 6.95 (m, 2H), 4.03 (s, 3H).

Step 7: methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate

To a solution of methyl 4-fluoro-5-((2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (1.82 g, 5.39 mmol) in DMF (10 mL) was added NBS (1.0 g, 5.65 mmol). After stirring for 4 h at ambient temperature, the reaction was quenched by saturated NH₄Cl (aq.). The solution was extracted with ethyl acetate (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL) successively, dried over Na₂SO₄ and concentrated in vacuo to give the desired product (yellow solid, 2.02 g, 90.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.84 (s, 1H), 8.60 (d, 1H), 7.59 (d, 1H), 7.29 (m, 1H), 6.77 (m, 1H), 4.04 (s, 3H).

Step 8: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid

To a solution of methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate (2.02 g, 4.85 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 2 mL, 10 mmol). After stirring at ambient temperature for 2 h, the reaction was treated with 1.0 M HCl (aq.) till the solution was acidic.

The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give the desired product (brown yellow solid, 1.85 g, 95% yield). ¹H NMR (400 MHz, CDCl₃): δ 13.90 (s, 1H), 8.80 (s, 1H), 8.55 (d, 1H), 7.56 (d, 1H), 7.27 (m, 1H), 6.75 (m, 1H).

Step 9: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (200 mg, 0.46 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.74 mmol) and EDCI (132 mg, 0.74 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (76 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄ filtered, and concentrated in vacuo. The crude product (191 mg) was used directly in the next step without further purification.

Step 10: 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of compound 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (191 mg, 0.39 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO₃ (aq.). The aqueous layer was washed with CH₂Cl₂ (10 mL×2). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) and gave the desired product as a yellow solid (150 mg, 66.5% yield for two steps). ¹H NMR (400 MHz, CD₃OD): δ 8.53 (s, 1H), 7.69 (s, 1H), 7.34 (d, 1H), 6.74 (m, 1H), 3.91 (m, 2H), 3.62 (m, 2H). MS APCI (+) m/z: 462.5 [M+H].

Example 20 Preparation of 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d][1,2,3]thiadiazole-6-carboxamide (Compound 20)

Step 1: N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((2-chloro-4-bromophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (200 mg, 0.49 mmol) in CH₂Cl₂ (10 mL) was added HOBt (100 mg, 0.74 mmol) followed by EDCI (140 mg, 0.74 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH₄Cl (aq.). The resultant mixture was extracted with CH₂Cl₂ (15 mL×3). The combined organic extracts was washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product (213 mg) was used directly in the next step without further purification.

Step 2: N-(2,3-dihydroxypropoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide

To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide (60 mg, 0.11 mmol) in CH₂Cl₂ (10 mL) was added 1.0 N HCl (aq., 1 mL, 1.0 mmol). The mixture was stirred for 1 h and neutralized with saturated sodium bicarbonate (aq.). The aqueous layer was extracted by CH₂Cl₂ (10 mL×2). The combined organic layers were washed by water (10 mL) and brine (10 mL) sequentially, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 20:1, v/v) to afford the desired product (yellow solid, 41 mg, 61.5% yield for two steps). ¹H NMR (400 MHz, CD₃OD): δ 11.13 (s, 1H), 8.59 (s, 1H), 7.66 (d, 1H), 7.34 (dd, 1H), 6.76 (m, 1H), 3.79 (m, 1H), 3.71 (m, 2H), 3.35 (m, 2H). MS APCI (+) m/z: m/z 492.8, [M+H].

Example 21 Preparation of N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide (Compound 21)

Step 1: 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (120 mg, 0.30 mmol) in t-BuOH (10 mL) was added DPPA (48 mg, 0.45 mmol) followed by triethylamine (60 mg, 0.60 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (100 mg, 83.9% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.14 (s, 1H), 8.01-7.99 (m, 1H), 7.89 (s, 1H), 7.83 (m, 1H), 7.59-7.55 (m, 1H).

Step 2: 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.14 mmol) in CH₂Cl₂ (3 mL) was added triethylamine (43 mg, 0.42 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (31 mg, 0.21 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (75 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.34 (s, 1H), 7.75-7.73 (d, 2H), 7.34 (m, 1H), 3.34 (m, 1H), 1.68 (m, 2H), 0.85 (m, 2H).

Step 3: N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide

To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (70 mg, 0.13 mmol) in THF (5 mL) was added potassium trimethylsilanolate (17 mg, 0.13 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (6 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product (40 mg, 60.1% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.86 (s, 1H), 8.37 (s, 1H), 7.73 (s, 1H), 7.60 (dd, 1H), 7.30 (dd, 1H), 6.45 (m, 1H), 2.77 (m, 1H), 1.01-0.99 (m, 2H), 0.89-0.86 (m, 2H). MS APCI (+) m/z: 508.7, [M+H].

Example 22 Preparation of 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide (Compound 22)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.12 mmol) in DCM (5 mL) was added triethylamine (24 mg, 0.23 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (32 mg, 0.17 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 89.9% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.36 (s, 1H), 7.76-7.74 (m, 2H), 7.35 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.11 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.11 mmol) in THF (5 mL) was added potassium trimethylsilanolate (14 mg, 0.11 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (50 mg, 87.3% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.24 (s, 1H), 7.65-7.63 (m, 2H), 7.31 (m, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 5.74-5.56 (m, 1H), 5.02 (m, 2H), 2.77-2.71 (m, 1H), 2.12-2.0 (m, 1H), 1.75-1.71 (m, 2H), 1.21-0.97 (m, 2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide (50 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide (12 mg, 0.09 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (30 mg, 56.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.67-7.64 (d, 2H), 7.32 (m, 1H), 7.03 (s, 1H), 6.85 (s, 1H), 4.40-4.26 (m, 2H), 4.20-4.10 (m, 1H), 3.75-3.60 (m, 1H), 3.60-3.50 (m, 1H), 2.62-2.50 (m, 2H), 0.92-0.82 (m, 4H). MS APCI (+) m/z: 583.5, [M+H].

Example 23 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide (Compound 23)

Step 1: 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (100 mg, 0.25 mmol) in t-BuOH (5 mL) was added DPPA (103 mg, 0.37 mmol) followed by triethylamine (76 mg, 0.75 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (90 mg, 90.7% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.67 (s, 1H), 7.96 (d, 1H), 7.76 (d, 1H), 7.50 (t, 1H).

Step 2: 7-(cyclopropylsulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.13 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (26 mg, 0.25 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (26 mg, 0.19 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (60 mg, 95% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 7.75-7.72 (d, 2H), 7.35 (m, 1H), 3.35 (m, 1H), 1.70 (m, 2H), 0.87 (m, 2H).

Step 3: N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide

To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.12 mmol) in THF (5 mL) was added potassium trimethylsilanolate (16 mg, 0.12 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product (30 mg, 52.7% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.25 (s, 1H), 8.02-7.98 (m, 1H), 7.85 (m, 1H), 7.60-7.56 (m, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 2.81-2.72 (m, 1H), 1.33 (m, 2H), 1.15 (m, 2H). MS APCI (+) m/z: 478.8, [M+H].

Example 24 Preparation of N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide (Compound 24)

Step 1: 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one

To a solution of 4-fluoro-5-(4-bromo-2-chlorophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (40 mg, 0.10 mmol) in DCM (5 mL) was added triethylamine (21 mg, 0.20 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (27 mg, 0.15 mmol) and DMAP (10 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO₃ (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (50 mg, 87.1% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.37 (s, 1H), 7.78-7.76 (d, 2H), 7.33 (m, 1H), 5.76-5.58 (m, 1H), 5.08 (m, 2H), 2.93-2.86 (m, 1H), 2.13-2.0 (m, 1H), 1.97-1.87 (m, 2H), 1.28-1.16 (m, 2H).

Step 2: 1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 7-((1-allylcyclopropyl)sulfonyl)-4-fluoro-5-(2-chloro-4-bromophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (50 mg, 0.09 mmol) in THF (5 mL) was added potassium trimethylsilanolate (12 mg, 0.09 mmol). The reaction was stirred at room temperature for 1 h and quenched with saturated NH₄Cl (aq.). The aqueous layer was extracted with EA (10 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the desired product (45 mg, 94.5% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.65-7.57 (m, 2H), 7.33 (m, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 5.72-5.57 (m, 1H), 5.05 (m, 2H), 2.79-2.72 (m, 1H), 2.12-2.05 (m, 1H), 1.76-1.71 (m, 2H), 1.21-0.98 (m, 2H).

Step 3: 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide

To a solution of 1-allyl-N-(4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide (45 mg, 0.09 mmol) in THF (5 mL) was added N-methylmorpholine-N-oxide (10 mg, 0.09 mmol) followed by osmium tetraoxide (5 mg, 0.02 mmol) and water (0.5 mL). The resultant was stirred at room temperature overnight. The mixture was concentrated and then diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO₃ (aq.) and brine sequentially, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel to give the product as white solid (20 mg, 41.7% yield). ¹H NMR (400 MHz, CDCl₃): δ 8.26 (s, 1H), 7.69-7.62 (d, 2H), 7.33 (m, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 4.40-4.25 (m, 2H), 4.22-4.12 (m, 1H), 3.75-3.62 (m, 1H), 3.61-3.52 (m, 1H), 2.62-2.51 (m, 2H), 0.95-0.82 (m, 4H). MS APCI (+) m/z: 552.9, [M+H].

Examples 25-33 Preparation of Compounds 25-33

Compounds 2533 were prepared following similar procedures used for compounds 1-8.

Compound 25

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.96 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.41 (m, 1H), 4.73 (s, 1H), 3.86 (m, 2H), 3.56 (m, 2H). MS APCI (+) m/z: 429.4 [M+H].

Compound 26

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.98 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.55 (d, J=9.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.41 (m, 1H), 4.71 (s, 1H), 3.82 (m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 418.4 [M+H].

Compound 27

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.95 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.54 (d, J=9.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.38 (m, 1H), 4.69 (s, 1H), 3.82 (m, 2H), 3.57 (m, 2H), 2.55 (s, 3H). MS APCI (+) m/z: 396.5 [M+H].

Compound 28

¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.97 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.55 (d, J=9.8 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.40 (m, 1H), 4.72 (s, 1H), 3.85 (m, 2H), 3.57 (m, 2H). MS APCI (+) m/z: 434.4 [M+H].

Compound 29

¹H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.95 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 6.42 (m, 1H), 4.75 (s, 2H), 3.68 (m, 4H), 3.38 (m, 1H). MS APCI (+) m/z: 506.3 [M+H].

Compound 30

¹H NMR (400 MHz, DMSO) δ 11.74 (s, 1H), 8.96 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.45 (m, 1H), 4.76 (s, 2H), 3.70 (m, 4H), 3.40 (m, 1H). MS APCI (+) m/z: 459.4 [M+H].

Compound 31

¹H NMR (400 MHz, DMSO) δ 11.75 (s, 1H), 8.95 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.58 (d, J=9.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.43 (m, 1H), 4.73 (s, 2H), 3.71 (m, 4H), 3.39 (m, 1H). MS APCI (+) m/z: 475.8 [M+H].

Compound 32

¹H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 8.93 (s, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.55 (d, J=9.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.41 (m, 1H), 3.73 (m, 2H), 0.51 (m, 1H), 0.25 (m, 4H). MS APCI (+) m/z: 486.2 [M+H].

Compound 33

¹H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 8.92 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.57 (d, J=9.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 6.43 (m, 1H), 3.75 (m, 2H), 0.52 (m, 1H), 0.26 (m, 4H). MS APCI (+) m/z: 455.8 [M+H].

Examples 34-42 Preparation of Compounds 43-51

Compounds 34-42 were prepared following similar procedures used for compounds 9-16.

Compound 34

¹H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 9.54 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.56 (d, 1H), 7.31 (d, 1H), 6.47 (m, 1H), 4.73 (s, 1H), 3.85 (m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 445.3 [M+H].

Compound 35

¹H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 9.53 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.56 (d, 1H), 7.33 (d, 1H), 6.50 (m, 1H), 4.74 (s, 1H), 3.85 (m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 434.4 [M+H].

Compound 36

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.54 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 6.45 (m, 1H), 4.73 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H), 2.51 (s, 3H). MS APCI (+) m/z: 412.5 [M+H].

Compound 37

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.55 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.52 (d, 1H), 7.28 (d, 1H), 6.43 (m, 1H), 4.75 (s, 1H), 3.83 (m, 2H), 3.55 (m, 2H). MS APCI (+) m/z: 450.5 [M+H].

Compound 38

¹H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 9.54 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 6.49 (m, 1H), 4.75 (s, 2H), 3.67 (m, 4H), 3.36 (m, 1H). MS APCI (+) m/z: 522.3 [M+H].

Compound 39

¹H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 9.55 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.57 (d, 1H), 7.31 (d, 1H), 6.50 (m, 1H), 4.74 (s, 2H), 3.68 (m, 4H), 3.35 (m, 1H). MS APCI (+) m/z: 475.3 [M+H].

Compound 40

¹H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 9.53 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.58 (d, 1H), 7.32 (d, 1H), 6.51 (m, 1H), 4.75 (s, 2H), 3.70 (m, 4H), 3.36 (m, 1H). MS APCI (+) m/z: 491.7 [M+H].

Compound 41

¹H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 9.55 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.60 (d, 1H), 7.31 (d, 1H), 6.52 (m, 1H), 3.72 (m, 2H), 0.50 (m, 1H), 0.25 (m, 4H). MS APCI (+) m/z: 471.7 [M+H].

Compound 42

¹H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 9.54 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.62 (d, 1H), 7.33 (d, 1H), 6.50 (m, 1H), 3.71 (m, 2H), 0.49 (m, 1H), 0.23 (m, 4H). MS APCI (+) m/z: 502.3 [M+H].

Examples 43-51 Preparation of Compounds 43-51

Compounds 43-51 were prepared following similar procedures used for compounds 17-24.

Compound 43

¹H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 7.35 (d, 1H), 7.23 (d, 1H), 6.37 (m, 1H), 4.72 (s, 1H), 4.04 (m, 2H), 3.78 (m, 2H). MS APCI (+) m/z: 446.3 [M+H].

Compound 44

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 7.38 (d, 1H), 7.24 (d, 1H), 6.41 (m, 1H), 4.70 (s, 1H), 4.04 (m, 2H), 3.79 (m, 2H). MS APCI (+) m/z: 435.4 [M+H].

Compound 45

¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 6.40 (m, 1H), 4.68 (s, 1H), 4.06 (m, 2H), 3.80 (m, 2H), 2.52 (s, 3H). MS APCI (+) m/z: 413.5 [M+H].

Compound 46

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.33 (d, 1H), 7.21 (d, 1H), 6.38 (m, 1H), 4.71 (s, 1H), 4.02 (m, 2H), 3.77 (m, 2H). MS APCI (+) m/z: 451.3 [M+H].

Compound 47

¹H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.35 (d, 1H), 7.24 (d, 1H), 6.41 (m, 1H), 4.70 (s, 1H), 4.03 (m, 4H), 3.68 (m, 1H). MS APCI (+) m/z: 523.3 [M+H].

Compound 48

¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.33 (d, 1H), 7.25 (d, 1H), 6.39 (m, 1H), 4.71 (s, 1H), 4.05 (m, 4H), 3.67 (m, 1H). MS APCI (+) m/z: 476.3 [M+H].

Compound 49

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 7.36 (d, 1H), 7.23 (d, 1H), 6.40 (m, 1H), 4.72 (s, 1H), 4.05 (m, 4H), 3.69 (m, 1H). MS APCI (+) m/z: 492.7 [M+H].

Compound 50

¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 7.35 (d, 1H), 7.25 (d, 1H), 6.41 (m, 1H), 3.70 (m, 2H), 0.51 (m, 1H), 0.26 (m, 4H). MS APCI (+) m/z: 503.4 [M+H].

Compound 51

¹H NMR (400 MHz, DMSO) δ 11.91 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 7.38 (d, 1H), 7.25 (d, 1H), 6.42 (m, 1H), 3.72 (m, 2H), 0.52 (m, 1H), 0.25 (m, 4H). MS APCI (+) m/z: 472.7 [M+H].

Example B-1 Cell Growth Inhibition Assays

Materials

-   CELLS: HT29, COLO205 and A375 cells were obtained from the Cell     Resource Center at the Institute of Basic Medical Research, Chinese     Academy of Medical Sciences. -   REAGENTS: DMEM/F12 (GIBCO), 0.25% trypsin (GIBCO), MTT (5 mg/ml),     DMSO, PBS -   INSTRUMENT: 37° C., 5% CO₂ cell incubator, the TECAN infinite TM200     Series multifunctional microplate reader, clean benches, cell     counting board -   CONSUMABLES: 96-well plates (CORING)     Methods 1 (HT29) -   1. When the HT29 cells reach their exponential phase of growth,     4×103 cells/well were plated into 96-well plates, the edge of plates     were filled with sterility PBS, at the same time, filled three holds     only with medium as blank group. -   2. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 24 h, and allowed to proliferate for reaching their     exponential phase of growth. -   3. Samples were dissolved in DMSO (dimethyl sulfoxide), the     concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10     μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture     medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100     nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control     group). The final DMSO concentration used was 1‰ of total volume of     medium in all treatments, including the control group.     -   Blank: medium     -   Control: the same dose of DMSO with experiment. Group, the DMSO         was diluted with cell perfect culture medium.     -   Experiment: the cells were treated with the concentration of 10         μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L. -   4. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 72 h. 20 μL of     3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)     reagent (5 mg/mL) in phosphate buffered serum (PBS) was added to     each well. -   5. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 4 h. Subsequently, the solution was aspirated and 150 uL     dimethyl sulfoxide was added to release the formed formazan crystals     from the living cells mitochondria into the solution. -   6. After moderated shaking for 3 min, absorbance was measured at 490     nm using microplate reader.     Methods 2 (A375) -   1. When the A375 cells reach their exponential phase of growth,     5×103 cells/well were plated into 96-well plates, the edge of plates     were filled with sterility PBS, at the same time, filled three holds     only with medium as blank group. -   2. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 24 h. Allowed to proliferate for reaching their     exponential phase of growth. -   3. Samples were dissolved in DMSO (Dimethyl Sulfoxide), the     concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10     μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture     medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100     nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control     group). The final DMSO concentration used was 1‰ of total volume of     medium in all treatments, including the control group. -   Blank: medium     -   Control: the same dose of DMSO with experiment group, the DMSO         was diluted with cell perfect culture medium     -   Experiment: the cells were treated with the concentration of 10         μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L -   4. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 72 h. 20 μL of     3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)     reagent (5 mg/mL) in phosphate buffered serum (PBS) was added to     each well. -   5. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 4 h. Subsequently, the solution was aspirated and 150 uL     dimethyl sulfoxide was added to release the formed formazan crystals     from the living cells mitochondria into the solution. -   6. After moderated shaking for 3 min, absorbance was measured at 490     nm using microplate reader.     Methods 3 (COLO205) -   1. When the COLO0205 cells reach their exponential phase of growth,     1×10⁴ cells/well were plated into 96-well plates, the edge of plates     were filled with sterility PBS, at the same time, filled three holds     only with medium as blank group. -   2. The plates were cultured in a humidified 5% CO2 incubator at     37° C. for 24 h. Allowed to proliferate for reaching their     exponential phase of growth. -   3. Samples were dissolved in DMSO (Dimethyl Sulfoxide), the     concentration of Samples is 10 mmol/L, 1 mmol/L, 100 μmol/L, 10     μmol/L, 1 μmol/L, 0.1 μmol/L, and further diluted with cell culture     medium. The final does concentration were 10 μmol/L, 1 μmol/L, 100     nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L, 0 nmol/L (the control     group). The final DMSO concentration used was 1‰ of total volume of     medium in all treatments, including the control group.     -   Blank: medium     -   Control: the same dose of DMSO with experiment group, the DMSO         was diluted with cell perfect culture medium     -   Experiment: the cells were treated with the concentration of 10         μmol/L, 1 μmol/L, 100 nmol/L, 10 nmol/L, 1 nmol/L, 0.1 nmol/L -   4. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 72 h. 20 μl of     3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)     reagent (5 mg/ml) in phosphate buffered serum (PBS) was added to     each well. -   5. The plates were cultured in a humidified 5% CO₂ incubator at     37° C. for 4 h. Subsequently, the solution was aspirated and 150 ul     dimethyl sulfoxide was added to release the formed formazan crystals     from the living cells mitochondria into the solution. -   6. After moderated shaking for 3 min, absorbance was measured at 490     nm using microplate reader.

The cell inhibition 1050 values obtained with the HT29 and A375 cells are shown in Table 5.

TABLE 5 Compound IC₅₀ (nM) No. HT29 A375 1 2.3 0.85 2 8.1 4.6 3 51.8 61.3 4 138 97.5 5 81.6 125 6 78.3 103 7 283 239 8 1092 738 9 1.0 0.79 10 18.5 11.2 11 51.2 61.4 12 738 174 13 98.3 207 14 201 119 15 184 99.8 16 1306 151 17 1.0 0.24 18 66.4 16.8 19 65.7 49.4 20 687 97.3 21 1078 1770 22 2620 1160 23 3640 562 24 4370 992

Example B-2 In Vivo Anti-Tumor Efficacy in HT29 Tumor Xenograft Model

Female BALB/c nude mice of 5-6 week old were used for all the in vivo efficacy studies. Mice were injected with HT29 human colon cancer cells at 5×10⁶ cells per 100 μL SFM into right flank. Tumor volumes were monitored by caliper measurement using the formula: tumor volume (mm³)=(w²×l)/2, where w=width and c=length in mm of the tumor. When the tumor volumes reached 150˜300 mm³, mice were randomized to treatment groups (5˜10 mice per group) to receive compounds (20 mg/kg doses) or vehicle by oral gavage once daily for 16 days. The tumor volumes and body weight were measured every 2-3 days for data analysis. Tumor growth inhibition (TGI) and body weight changes were calculated compared to the vehicle treated groups. TGI represents the percent volume differential between the treated and control tumors at the time vehicle tumors exceeded a volume of 1,000 based on formula TGI (%)=(1−(T−To)/(C−Co))*100%.

The results for Compounds 1, 3, 9, 11, 17 and 19 are shown in FIG. 1. The results show that the human colon HT-29 xenograft was highly sensitive to Compounds 9 and 17, which demonstrated 95.1% TGI for Compound 9 at 20 mg/kg and 88.75% TGI for 17 at 20 mg/kg respectively after 16 days of treatment. Compounds 1, 11 and 19 also showed significant inhibition of HT29 xenograft growth in nude mice at 20 mg/kg with TGI at 55.1%, 68.51% and 50.9% respectively. Compound 3 at 20 mg/kg showed no significant effects on HT29 cancer cell growth with TGI at 32.3% in nude mice after 16 days treatment. Reference compound AZD6244 showed inhibition of HT29 xenograft growth in nude mice at 20 mg/kg with TGI at 48.3% after 16 days treatment.

Example B-3 In Vivo Anti-Tumor Efficacy in COLO205 Tumor Xenograft Model

The animal use and care protocol was approved by Sundia Institutional Animal Care and Use Committee. Male athymic nude mice (nu/nu; 6 weeks of age) were obtained from Beijing HFK Bioscience CO., LTD. All animals were fed with commercial diet and water ad libitum for 1 week before the study.

Each mouse was inoculated s.c. in the flank with COLO 205 tumor fragment (˜1 mm³). When rumors reached the appropriate size for staging (170 mm³ or as indicated in data graphs), mice were randomized to eight groups (n=6) that received the following treatments: (a) 20% SBE-β-CD in purity water vehicle, (b) AZD6244 at 10 mg/kg QD, (c) test compound 19 at 10 mg/kg QD, (d) test compound 1 at 10 mg/kg QD, (e) test compound 3 at 20 mg/kg QD, (f) test compound 9 at 5 mg/kg QD, (g) test compound 11 at 10 mg/kg QD, (h) test compound 17 at 5 mg/kg QD. Mice received treatments by gavage (10 mL/kg body weight) for the duration of the study. Tumors were measured twice a week using calipers and their volumes calculated using the formula (width²×length)/2. In this experiment, tumors were staged on day 0, the day of first treatment. The Reference Compounds and the test compounds were formulated in 20% SBE-β-CD.

The tumor growth inhibition ratio was calculated using the formula: TGI=100×[(tumor volume_(final) for the vehicle-treated group−tumor volume_(final) for the compound-treated group)/tumor volume_(final) for the vehicle-treated group]. Tumor growth data are expressed as mean tumor volumes±S.E. Differences were considered significant at P<0.05 and statistical analysis was done using Microsoft Excel.

After 18 days consecutive treatments (QD×18 days), the Reference compound 1 inhibited 72.80% (P<0.01) of tumor growth, compared with the vehicle control group. The test compound 1, 3, 9, 11, 17 and 19 inhibited 91.22% (P<0.01), 47.11% (P<0.05), 94.70% (P<0.01), 82.14% (P<0.01), 95.35% (P<0.01) and 86.22% (P<0.01) of tumor growth, respectively, compared with the vehicle control group.

The results for Compounds 1, 3, 9, 11, 17 and 19 are shown in FIG. 2.

Example B-4 Inhibition of Interleukin-4 (IL-4)

Method:

-   1. Take spleens of BALB/c gene reported mice, culture in RPMI1640     medium (HyClone). -   2. Spleen will be ground into single cell suspension, add red blood     cell lysis buffer (sigma) to suspension, for cracking the red blood     cells. -   3. The cell suspension was filtered, and suspended in 1640 medium     containing 10% serum. -   4. Dissolved compounds with DMSO and diluted with RPMI1640 medium     containing 10% serum, diluted to a final concentration of 200 nM. -   5. According with the concentration of 4×106/mL, 100 μL/well,     calculate the required total number of cells, suspended in the RPMI     1640 medium containing 10% serum. in the cell suspension, added ConA     (Concanavalin A, sigma) (final concentration for 2.5 ng/mL), IL-2     (interleukin-2, R & D) (final concentration of 2 ng/mL), IL-4     (interleukin-4, PeproTech) (final concentration of 20 ng/mL) into     the cell suspension. After mixing, cells were added to 96 well     plates, every hole is 100 μL. Joined the compound solution, 100     μL/well, the cell final concentration is 2×106/mL, the compounds     final concentration is 100 nM. Each compound and control is     three-hole wells, cultured at 37° C. for 48 h. -   6. After 48 h, the plates removed from the incubator and each well     was collected in the flow tube (BD). -   7. Added cells to ice pre-cooling of PBS (phosphate buffer solution)     solution to wash, and in 100 μL of PBS, join the fluorescent     antibody CD4 0.5 μL, put in ice 15 min avoid light. -   8. After dyeing wash antibodies with the ice pre-cooling PBS     solution. And prepare for flow cytometric detection. -   9. Using flow cytometry (BD FACS calibur) select the CD4+ cell     populations, and detect GFP+ cells accounted for the percentage of     CD4+ cells, to determine the impact of compounds on IL-4. -   10. The inhibition rate of IL-4(%)=(Control %−compounds %)/control     %×100%.

Control was DMSO and its concentration was same as the final concentration of test compounds. Compounds 1, 3, 9, 11, 17, 19, 25, 34 and 43 showed up to 50% IL-4 inhibition.

Example B-5 Inhibition of TNF-α Expression

Method:

-   1. Take spleens of BALB/c gene reported mice, cultured in RPMI1640     medium (HyClone). Spleen was ground into single cell suspension,     added red blood cell lysis buffer (sigma) to suspension, for     cracking the red blood cells -   2. The cell suspension was filtered, and suspended in 1640 medium     containing 10% serum (HyClone), the cell final concentration was     4×10⁶/mL, added LPS to medium and final concentration was 200 ng/mL. -   3. Dissolved compounds with DMSO and diluted with RPMI1640 medium     containing 10% serum, diluted to a final concentration of 200 nM. -   4. Cells were added to 96 well plates, every hole was 100 μL. Joined     the compound solution, 100 μL/well, the cell final concentration was     2×106/mL, the compounds final concentration was 100 nM. Each     compound and control is three-hole wells. -   5. Cultured at 37° C. for 24 h. -   6. Centrifuged at 1400 rmp, 7 min by Cell plate centrifuge     (Eppendorf 5810R), drew the supernatant and placed in the new     96-well plates, placed at 4° C. to save. -   7. Using ELISA (enzyme-linked immunosorbent assay) technique for the     determination of the amount of TNF-α in the 24 hours.

Control was DMSO and its concentration was same as the final concentration of test compounds. Compounds 1, 3, 9, 11, 17, 19, 25, 34 and 43 showed up to 40% inhibition.

All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. 

The invention claimed is:
 1. A compound of the formula (I):

or a salt, prodrug or solvate thereof, wherein: X¹ is CR¹¹ or N; X² is O, S or carbonyl; R¹, R², R⁴ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl; R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl; R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl; each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl; R⁶ is —C(O)N(R⁸)OR⁷ or —NHSO₂R¹⁰; R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group; R⁸ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; R¹⁰ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; and R¹¹ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl or C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl; wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.
 2. The compound of claim 1, or a salt thereof, wherein X² is O or S.
 3. The compound claim 1, or a salt thereof, wherein R¹ is halo.
 4. The compound claim 1, or a salt thereof, wherein R² is hydrogen.
 5. The compound of claim 1, or a salt thereof, wherein R³ is iodo or bromo.
 6. The compound of claim 1, or a salt thereof, wherein R⁴ is hydrogen.
 7. The compound of claim 1, or a salt thereof, wherein R⁵ is fluoro.
 8. The compound of claim 1, or a salt thereof, wherein R⁶ is —C(O)N(R⁸)OR⁷.
 9. The compound of claim 8, or a salt thereof, wherein R⁸ is hydrogen.
 10. The compound of claim 1, or a salt thereof, wherein the compound is selected from the group consisting of: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide; N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)cyclopropanesulfonamide; N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)cyclopropanesulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; 4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide; 5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]oxazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide; N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d]thiazole-6-carboxamide; N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropanesulfonamide; 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]thiazol-6-yl)cyclopropane-1-sulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)cyclopropanesulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; 4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide; 4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide; 4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide; 5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide; 5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide; 5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide; and 5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d]thiazol-6-carboxamide.
 11. The compound of claim 1, or a salt thereof, wherein the compound is selected from the group consisting of: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]oxazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-bromophenyl)amino)-N-(2-hydroxyethoxy)benzo[d]thiazol-6-carboxamide; and 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d]thiazole-6-carboxamide.
 12. The compound of claim 1, wherein the compound is of the formula (J):

or a salt thereof, wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined in claim
 1. 13. A compound of the formula (J-1):

or a salt thereof, wherein: R¹ and R⁵ are independently hydrogen, halo, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, amino, carboxy, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl; R³ is hydrogen, halo, cyano, nitro, azido, hydroxy, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, mercapto, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d), —C(O)OR^(b), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl; R^(a) is C₁-C₁₀ alkyl or C₆-C₁₄ aryl; each R^(b), R^(c) and R^(d) is independently hydrogen or C₁-C₁₀ alkyl; and R⁷ is hydrogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl C₁-C₁₀ alkyl or C₁-C₁₀ alkyl C₃-C₁₀ cycloalkyl; wherein each C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or C₃-C₁₀ cycloalkyl moiety may be unsubstituted or substituted with one or more groups independently selected from the group consisting of hydroxy, oxo, halo, cyano, nitro, trifluoromethyl, azido, amino, carboxy and mercapto.
 14. The compound of claim 13, or a salt thereof, wherein: R¹ is halo or unsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted or substituted C₁-C₁₀ alkyl; and R⁷ is hydrogen, unsubstituted or substituted C₁-C₁₀ alkyl or unsubstituted or substituted C₃-C₁₀ cycloalkyl.
 15. The compound of claim 12, wherein the compound is of the formula (J-2) or (J-3):

or a salt thereof.
 16. The compound of claim 15, or a salt thereof, wherein: R¹ is halo or unsubstituted or substituted C₁-C₁₀ alkyl; R³ is halo, unsubstituted or substituted C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo-substituted C₁-C₁₀ alkoxy, acyloxy, C₁-C₁₀ alkylthio, halo-substituted C₁-C₁₀ alkylthio, —SO₂R^(a), —SO₂N(R^(c))R^(d), —N(R^(c))R^(d) or —C(O)OR^(b); R⁵ is hydrogen, halo or unsubstituted or substituted C₁-C₁₀ alkyl; R⁷ is C₁-C₁₀ alkyl substituted with at least one hydroxy group; and R¹¹ is hydrogen.
 17. The compound of claim 15, or a salt thereof, wherein: R¹ is fluoro or chloro; R³ is iodo or bromo; R⁵ is fluoro; and R⁷ is selected from the group consisting of 2-hydroxyethyl, 3-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl and 1,3-dihydroxy-2-propyl.
 18. The compound of claim 12, wherein the compound is of the formula (J-4):

or a salt thereof.
 19. A pharmaceutical composition comprising a compound of claim 1, or a salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier.
 20. A kit comprising a compound of claim 1, or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 21. A method of making a compound of the formula (J), or a salt thereof, comprising coupling of a compound of the formula (G), or a salt thereof, with a hydroxylamine derivative of the formula R⁷O—N(R⁸)H or a salt thereof:

wherein X¹, X², R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined in claim 1, and R¹⁴ is hydrogen, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl.
 22. The method of claim 21, wherein: (i) X¹ is N and X² is S:

further comprising converting a compound of the formula (F-1a) or a salt thereof to the compound of the formula (G-1a) or a salt thereof:

wherein R¹⁵ is allyl, benzyl, benzyl substituted with 1 to 3 methoxy groups, C₁-C₅ alkyl or —SiR¹⁶R¹⁷R¹⁸ where R¹⁶, R¹⁷ and R¹⁸ are independently selected from C₁-C₁₀ alkyl and C₆-C₁₄ aryl; (ii) X¹ is CR¹¹ and X² is O:

further comprising converting a compound of the formula (F-2a) or a salt thereof to the compound of the formula (G-2a) or a salt thereof:

or (iii) X¹ is CR¹¹ and X² is S:

further comprising converting a compound of the formula (F-3a) or a salt thereof to the compound of the formula (G-3a) or a salt thereof:


23. The compound of claim 13, or a salt thereof, wherein the compound is selected from the group consisting of: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide; N-(2,3-dihydroxypropoxy)-4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-N-(2,3-dihydroxypropoxy)-4-fluorobenzo[d][1,2,3]thiadiazole-6-carboxamide; N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide; 1-(2,3-dihydroxypropyl)-N-(4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazol-6-yl)cyclopropane-1-sulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)cyclopropanesulfonamide; N-(5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d][1,2,3]thiadiazol-6-yl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide; 4-fluoro-5-((2-fluoro-4-trifluoromethylphenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide; 4-fluoro-5-((2-fluoro-4-methylthiophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide; 5-((4-trifluoromethoxy-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazol-6-carboxamide; 5-((2-fluoro-4-iodophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide; 5-((4-bromo-2-fluorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide; 5-((4-bromo-2-chlorophenyl)amino)-N-(1,3-dihydroxy-isopropoxy)-4-fluorobenzo[d][1,2,3]thiadiazol-6-carboxamide; 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol-6-carboxamide; and 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)-N-cyclopropylmethyl-benzo[d][1,2,3]thiadiazol-6-carboxamide.
 24. The compound of claim 13, or a salt thereof, wherein the compound is selected from the group consisting of: 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide; 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide; and 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide.
 25. A pharmaceutical composition comprising a compound of claim 11, or a salt thereof, and a pharmaceutically acceptable carrier. 